Retroviral protease inhibitors

ABSTRACT

Hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

This is a divisional of application Ser. No. 07/886,663 filed May 20,1992, now abandoned, which is a continuation-in-part of application Ser.No. 07/789,643, filed Nov. 14, 1991, now abandoned, which is acontinuation-in-part of application Ser. No. 07/615,210, filed Nov. 19,1990, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to hydroxyethylamine protease inhibitor compounds, acomposition and method for inhibiting retroviral proteases such as humanimmunodeficiency virus (HIV) protease and for treatment, such asprophylactic treatment or of a retroviral infection, e.g., an HIVinfection. The subject invention also relates to processes for makingsuch compounds as well as to intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitreplication of structural proteins and, more importantly, the retroviralprotease itself. In this manner, retroviral replication proteases can beeffectively inhibited.

Several classes of mimetic compounds have been proposed, particularlyfor inhibition of proteases, such as for inhibition of HIV protease.Such mimetics include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al,"Rational Design of Peptide-Based Proteinase Inhibitors, "Science, 248,358 (1990); and Erickson et al, "Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,"Science, 249, 527 (1990).

Several classes of mimetic compounds are known to be useful asinhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat.No. 4,599,198; U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B.2,200,115 and U.S. SIR H725. However, it is known that, although reninand HIV proteases are both classified as aspartyl proteases, compoundswhich are effective renin inhibitors generally cannot be predicted to beeffective HIV protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula: ##STR1## or apharmaceutically acceptable salt, prodrug or ester thereof wherein:

A represents radicals represented by the formulas: ##STR2## wherein Rrepresents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,aryloxycarbonylalkyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl,heteroaryloxyalkyl, hydroxyalkyl, aminoalkanoyl, aminocarbonyl, andmono- and disubstituted aminoalkanoyl and mono- and disubstitutedaminocarbonyl radicals wherein the substituents are selected from alkyl,aryl, arolkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkyalkyl radicals, or in the case of adisubstituted aminoalkanoyl, said substitutents along with the nitrogenatom to which they are attched form a heterocyclyl or heteroarylradical;

R' represents hydrogen and radicals as defined for R³ or R and

R' together with the nitrogen to which they are attached form aheterocycloalkyl or heteroaryl radical or when A is A1, R' representshydrogen and aminocarbonyl radicals as defined for R³ andaralkoxycarbonylalkyl and aminocarbonylalkyl and aminocarbonyl radicalswherein said amino group may be mono- or disubstituted withsubstitutents selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylclkyl, heteroaryl, heteroaralkyl, hetercycloalkyl andheterocycloalkylalkyl radicals;

t represents either 0 or 1;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CO₂ CH₃, --CH₂ CO₂ CH₃,--CONH₂, --CONHCH₃, --CON(CH₃)₂, --CH₂ CONHCH₃, --CH₂ CON(CH₃)₂,--(CH₃)₂ (SCH₃), --C(CH₃)₂ (S O!CH₃), --C(CH₃)₂ (S O!₂ CH₃), alkyl,haloalkyl, alkenyl, alkynyl and cycloalkyl radicals and amino acid sidechains selected from asparagine, S-methyl cysteine and the correspondingsulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine,allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine,histidine, norleucine, glutamine, valine, threonine, serine, asparticacid, beta-cyano-alanine and allo-threonine side chains;

R^(1') and R^(1") independently represent hydrogen and radicals asdefined for R¹, or one of R^(1') and R^(1"), together with R¹ and thecarbon atoms to which they are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from --OR⁹, --SR⁹, --NO₂ and halogen radicals, wherein R⁹represents hydrogen and alkyl radicals;

R³ represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical;

X represents O and C(R¹⁷) where R¹⁷ represents hydrogen and and alkylradicals;

X' represents O, N and C(R¹⁷); provided that when X and/or X' is absent,R⁵ and/or R³⁴ are absent;

Y, Y', and Y" independently represent O, S and NR¹⁵ wherein R¹⁵represents radicals as defined for R³ ;

R⁴ and R⁵ independently represent hydrogen and radicals as defined byR³, or R⁴ and R⁵ together with the carbon atom to which they are bondedrepresent cycloalkyl, heterocycloalkyl, heteroaryl and aryl radicals;

R⁶ represents hydrogen and alkyl radicals;

R²⁰, R²¹, R³⁰, R³¹ and R³² represent radicals as defined for R¹, or oneof R¹ and R³⁰ together with one of R³¹ and R³² and the carbon atoms towhich they are attached form a cycloalkyl radical; and

R³³ and R³⁴ independently represent hydrogen and radicals as defined forR³, or R³³ and R³⁴ together with X' represent cycloalkyl, aryl,heterocyclyl and heteroaryl radicals.

A preferred class of retroviral inhibitor compounds of the presentinvention are those represented by the formula: ##STR3## or apharmaceutically acceptable salt, prodrug or ester thereof, preferablywherein the stereochemistry about the hydroxy group is designated as(R); wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,aryloxycarbonylalkyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heteroaralkanoyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl,hetroaryloxycarbonyl, heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl,heteroaryloxyalkyl, hydroxyalkyl, aminoalkanoyl, aminocarbonyl and mono-and disubstituted aminoalkanoyl and mono- and disubstitutedaminocarbonyl radicals wherein the substituents are selected from alkyl,aryl, arolkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkyalkyl radicals, or in the case of adisubstituted aminoalkanoyl, said substitutents along with the nitrogenatom to which they are attched form a heterocyclyl or heteroarylradical;

R' represents hydrogen and radicals as defined for R³ or R and R'together with the nitrogen to which they are attached form aheterocycloalkyl or heteroaryl radical, or when A is A1, R' representshydrogen and radicals as defined for R³ and aralkoxycarbonylalkyl andaminocarbonylalkyl radicals wherein said amino group may be mono- ordisubstituted with substitutents selected from alkyl, aryl, atalkyl,cycloalkyl, cycloalkylclkyl, heteraryl, heteroaralkyl, hetercycloalkyland heterocycloalkylalkyl radicals;

R¹ represents hydrogen, --CH₂ SO₂ NH₂, --CO₂ CH₃, --CH₂ CO₂ CH₃,--CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ CONHCH₃, --CH₂ CON(CH₃)₂, C(CH₃)₂(SCH₃), C(CH₃)₂ (S O!CH₃), C(CH₃)₂ (S O!₂ CH₃), alkyl, haloalkyl,alkenyl, alkynyl and cycloalkyl radicals and amino acid side chainsselected from asparagine, S-methyl cysteine and the correspondingsulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine,allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine,histidine, norleucine, glutamine, valine, threonine, serine, asparticacid, beta-cyano-alanine and allo-threonine side chains;

R^(1') and R^(1") independently represent hydrogen and radicals asdefined for R¹, or one of R^(1') and R^(1"), together with R¹ and thecarbon atoms to which they are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl radicals, --NO₂, OR⁹ and SR⁹ wherein R⁹ representshydrogen and alkyl radicals, and halogen radicals;

R³ represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical;

R⁴ and R⁵ independently represent hydrogen and radicals as defined byR³, or together with a carbon atom to which they are bonded representcycloalkyl, heterocycloalkyl, heteroaryl and aryl radicals;

t represents 0 or 1;

X represents O and C (R¹⁷) wherein R¹⁷ represents hydrogen and alkylradicals; provided that when X is O, R⁵ is absent; and

Y and Y' independently represent O, S, and NR¹⁵ wherein R¹⁵ representsradicals as defined for R³. Preferably, Y and Y' represent O.

Preferably, R³ represents radicals as defined above which contain noα-branching, e.g., as in an isopropyl radical or a t-butyl radical. Thepreferred radicals are those which contain a --CH₂ -- moiety between thenitrogen and the remaining portion of the radical. Such preferred groupsinclude, but are not limited to, benzyl, isobutyl, n-butyl, isoamyl,cyclohexylmethyl and the like.

Another preferred class of compounds are those represented by theformula: ##STR4## or a pharmaceutically acceptable salt, prodrug orester thereof wherein t, X, Y, Y', R', R¹, R², R³, R⁴, R⁵, R²⁰ and R²¹are as defined above.

Yet another preferred class of compounds are those represented by theformula: ##STR5## or a pharmaceutically acceptable salt, prodrug orester thereof wherein t, X, X', Y, Y', Y", R¹, R², R³, R⁴, R⁵, R³⁰, R³¹,R³², R³³ and R³⁴ are as defined above.

As utilized herein, the term "alkyl", alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to about 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm "alkenyl", alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to about 8carbon atoms. Examples of suitable alkenyl radicals include ethenyl,propenyl, allyl, 1,4-butadienyl and the like. The term alkynyl, alone orin combination, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to about 10 carbon atoms.Examples of alkynyl radicals include ethynyl, propynyl (propargyl),butynyl and the like. The term "alkoxy", alone or in combination, meansan alkyl ether radical wherein the term alkyl is as defined above.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like. The term "cycloalkyl" means an alkyl radical which containsfrom about 3 to about 8 carbon atoms and is cyclic. The term"cycloalkylalkyl" means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from about 3 to about 6, carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like. The term "aryl", alone or in combination, meansa phenyl or naphthyl radical which optionally carries one or moresubstituents selected from alkyl, alkoxy, halogen, hydroxy, amino andthe like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, and the like. The term "aralkyl", alone or incombination, means an alkyl radical as defined above in which onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, 2-phenylethyl and the like. The term "aralkoxy carbonyl", aloneor in combination, means a radical of the formula --C(O)--O-aralkyl inwhich the term "aralkyl" has the significance given above. An example ofan aralkoxycarbonyl radical is benzyloxycarbonyl. The term "aryloxy"means a radical of the formula aryl-O in which the term aryl has thesignificance given above. The term "alkanoyl", alone or in combination,means an acyl radical derived from an alkanecarboxylic acid, examples ofwhich include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, andthe like. The term "cycloalkylcarbonyl" means an acyl group derived froma monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.The term "aralkanoyl" means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4 -aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term "aroyl" means an acyl radical derived from anaromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-=carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, orheterocyclylalkyl group or the like is a saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic heterocycle which containsone or more hetero atoms selected from nitrogen, oxygen and sulphur,which is optionally substituted on one or more carbon atoms by halogen,alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom(i.e., --NH--) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl orphenylalkyl or on a tertiary nitrogen atom (i.e. =N-) by oxido and whichis attached via a carbon atom. The heteroaryl portion of a heteroaroyl,heteroaryloxycarbonyl, or a heteroaralkoxy carbonyl group or the like isan aromatic monocyclic, bicyclic, or tricyclic heterocycle whichcontains the hetero atoms and is optionally substituted as defined abovewith respect to the definition of heterocyclyl. Examples of suchheterocyclyl and heteroaryl groups are pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g.,imidazol 4-yl, 1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl,pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl,thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g.,2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl(e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl(e.g., 1,2,3,4-tetrahydro-2-quinolyl, etc.),1,2,3,4-tetrahydroisoquinolinyl (e.g.,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, benzofurancarbonyl, benzimidazolyl radicals and the like.The term "cycloalkylalkoxycarbonyl" means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O--COOHwherein cycloalkylalkyl has the significance given above. The term"aryloxyalkanoyl" means an acyl radical of the formula aryl-O-alkanoylwherein aryl and alkanoyl have the significance given above. The term"heterocyclyloxycarbonyl" means an acyl group derived fromheterocyclyl-O--COOH wherein heterocyclyl is as defined above. The term"heterocyclyl alkanoyl" is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term "heterocyclylalkoxycarbonyl"means an acyl radical derived from a heterocyclyl-substitutedalkane-O--COOH wherein heterocyclyl has the significance given above.The term "heteroaryloxycarbonyl" means an acyl radical derived from acarboxylic acid represented by heteroaryl-O--COOH wherein heteroaryl hasthe significance given above. The term "aminocarbonyl" alone or incombination, means an amino-substituted carbonyl (carbamoyl) groupderived from an amino-substituted carboxylic acid wherein the aminogroup can be a primary, secondary or tertiary amino group containingsubstituents selected from hydrogen, and alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term"aminoalkanoyl" means an acyl group derived from an amino-substitutedalkanecarboxylic acid wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term "haloalkyl" means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term "halogen"means fluorine, chlorine, bromine or iodine. The term "leaving group"generally refers to groups readily displaceable by a nucleophile, suchas an amine, a thiol or an alcohol nucleophile. Such leaving groups arewell known and include carboxylates, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates --OR and --SR andthe like. Preferred leaving groups are indicated herein whereappropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the stereochemistry about the hydroxyl group isdesignated as (R). However, such procedures are generally applicable, asillustrated, to those compounds of opposite configuration, e.g., wherethe stereochemistry about the hydroxyl group is (S).

Preparation of Compounds of Formula II

The compounds of the present invention represented by Formula II abovecan be prepared utilizing the following general procedure. AnN-protected chloroketone derivative of an amino acid having the formula:##STR6## wherein P represents an amino protecting group, and R² is asdefined above, is reduced to the corresponding alcohol utilizing anappropriate reducing agent. Suitable amino protecting groups are wellknown in the art and include carbobenzoxy, butyryl, t-butoxycarbonyl,acetyl, benzoyl and the like. A preferred amino protecting group iscarbobenzoxy. A preferred N-protected chloroketone isN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone. A preferredreducing agent is sodium borohydride. The reduction reaction isconducted at a temperature of from -10° C. to about 25° C., preferablyat about 0° C., in a suitable solvent system such as, for example,tetrahydrofuran, and the like. The N-protected chloroketones arecommercially available from Bachem, Inc., Torrance, Calif.Alternatively, the chloroketones can be prepared by the procedure setforth in S. J. Fittkau, J. Prakt. Chem., 315, 1037 (1973), andsubsequently N-protected utilizing procedures which are well known inthe art.

The resulting alcohol is then reacted, preferably at room temperature,with a suitable base in a suitable solvent system to produce anN-protected amino epoxide of the formula: ##STR7## wherein P and R² areas defined above. Suitable solvent systems for preparing the aminoepoxide include ethanol, methanol, isopropanol, tetrahydrofuran,dioxane, and the like including mixtures thereof. Suitable bases forproducing the epoxide from the reduced chloroketone include potassiumhydroxide, sodium hydroxide, potassium t-butoxide, DBU and the like. Apreferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared starting withan L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected L-amino acid esterof the formula: ##STR8## wherein P, p¹ and p² independently representhydrogen and amino-protecting groups as defined above with respect to P,provided that p¹ and p² are not both hydrogen; and R² is as definedabove.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at -78° C. in asuitable solvent such as toluene. The resulting alcohol is thenconverted, by way of a Swern Oxidation, to the corresponding aldehyde ofthe formula: ##STR9## wherein p¹, p² and R² are as defined above Thus, adichloromethane solution of the alcohol is added to a cooled (-75° to-68° C.) solution of oxalyl chloride in dichloromethane and DMSO indichloromethane and stirred for 35 minutes.

The aldehyde resulting from the Swern Oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹ CH₂ X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to -78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas: ##STR10## The diastereomers can be separated by chromatographyor, alternatively, once reacted in subsequent steps the diastereomericproducts can be separated.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of theformula:

    R.sup.3 NH.sub.2

wherein R³ is hydrogen or is as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 10° C. toabout 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³ NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formula: ##STR11##wherein P, R² and R³ are as described above.

Where X is either O or C, the appropriate analogs can be prepared byreacting the above described amino alcohol with an acid chloride oranhydride to form the analog wherein X is C, or with a chloroformate orpyrocarbonate where X is O. Procedures for reacting these compounds withan amine are well known in the art. Examples of such compounds includet-butylacetyl chloride, acetic anhydride, t-butyl pyrocarbonate, andN-butyl chloroformate. These analogs can be represented by the formulas:##STR12##

The derivative of the amino alcohol and the corresponding sulfur analogcan be represented by the formula: ##STR13##

Following preparation of such derivatives, the amino protecting group Pis removed under conditions which will not affect the remaining portionof the molecule. These methods are well known in the art and includeacid hydrolysis, hydrogenolysis and the like. A preferred methodinvolves removal of the protecting group, e.g., removal of acarbobenzoxy group, by hydrogenolysis utilizing palladium on carbon in asuitable solvent system such as an alcohol, acetic acid, and the like ormixtures thereof. Where the protecting group is a t-butoxycarbonylgroup, it cab be removed utilizing an inorganic or organic acid, e.g.,HCl or trifluoroacetic acid, in a suitable solvent system, e.g., dioxaneor methylene chloride. The resulting produce is the amine saltderivative. Following neutralization of the salt, the amine is thenreacted with an amino acid or corresponding derivative thereofrepresented by the formula (PN CR¹ 'R.sup. "!_(t) CH(R¹)COOH) wherein t,R¹, R^(1') and R^(1") are as defined above, to produce the antiviralcompounds of the present invention having the formula: ##STR14## whereint, X, P, R¹, R^(1'), R^(1"), R², R³, R⁴, R⁵ and Y are as defined above.Preferred protecting groups in this instance are a benzyloxycarbonylgroup or a t-butoxycarbonyl group. Where the amine is reacted with aderivative of an amino acid, e.g., when t=1 and R^(1') and R^(1") areboth H, so that the amino acid is a β-amino acid, such β-amino acids canbe prepared according to the procedure set forth in a copendingapplication, U.S. Ser. No. 07/345,808. Where t is 1, one of R^(1') andR^(1") is H and R¹ is hydrogen so that the amino acid is a homo-β-aminoacid, such homo-β-amino acids can be prepared by the procedure set forthin a copending application, U.S. Ser. No. 07/853,561. Where t is O andR¹ is alkyl, cycloalkyl, --CH₂ SO₂ NH₂ or an amino acid side chain, suchmaterials are well known and many are commercially available fromSigma-Aldrich.

The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula: ##STR15## wherein R is asdefined above and L is an appropriate leaving group such as a halide.Preferably, where R¹ is a side chain of a naturally occurring α-aminoacid, R is a 2-quinoline group derived fromN-hydroxysuccinimide-2-quinoline carboxylate, i.e., L is hydroxysuccinimide. A solution of the free amine (or amine acetate salt) andabout 1.0 equivalent of the carboxylate are mixed in an appropriatesolvent system and optionally treated with up to five equivalents of abase such as, for example, N-methylmorpholine, at about roomtemperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethylformamide, and the like, includingmixtures thereof.

Preparation of Compounds of Formula III

A mercaptan of the formula R'SH is reacted with a substitutedmethacrylate of the formula: ##STR16## by way of a Michael Addition. TheMichael Addition is conducted in a suitable solvent and in the presenceof a suitable base, to produce the corresponding thiol derivativerepresented by the formula: ##STR17## wherein R' and R¹ representradicals defined above; R²⁰ and R²¹ represent hydrogen and radicals asdefined for R¹ ; and R²² represents radicals as defined by R³. Suitablesolvents in which the Michael Addition can be conducted include alcoholssuch as, for example, methanol, ethanol, butanol and the like, as wellas ethers, e.g., THF, and acetonitrile, DMF, DMSO, and the like,including mixtures thereof. Suitable bases include Group I metalalkoxides such as, for example sodium methoxide, sodium ethoxide, sodiumbutoxide and the like as well as Group I metal hydrides, such as sodiumhydride, including mixtures thereof.

The thiol derivative is converted into the corresponding sulfone of theformula: ##STR18## by oxidizing the thiol derivative with a suitableoxidation agent in a suitable solvent. Suitable oxidation agentsinclude, for example, hydrogen peroxide, sodium meta-perborate, oxone(potassium peroxy monosulfate), meta-chloroperoxybenzoic acid, and thelike, including mixtures thereof. Suitable solvents include acetic acid(for sodium meta-perborate) and, for other peracids, ethers such as THFand dioxane, and acetonitrile, DMF and the like, including mixturesthereof.

The sulfone is then converted to the corresponding free acid of theformula: ##STR19## utilizing a suitable base, e.g., lithium hydroxide,sodium hydroxide and the like, including mixtures thereof, in a suitablesolvent, such as, for example, THF, acetonitrile, DMF, DMSO, methylenechloride and the like, including mixtures thereof.

The free acid is then coupled, utilizing, as described above, procedureswell known in the art, to the urea derivative, or analog thereof, of anamino alcohol which is described above for the preparation of compoundsof Formula II. The resulting product is a compound represented FormulaIII.

Alternatively, one can couple the urea isostere to the commerciallyavailable acid, ##STR20## remove the thioacetyl group with a suitablebase, such as hydroxide, or an amine, such as ammonia, and then reactthe resulting thiol with an alkylating agent, such as an alkyl halide,tosylate or mesylate to afford compounds at the following structure:##STR21##

The sulfur can then be oxidized to the corresponding sulfone usingsuitable oxidizing agents, as described above, to afford the desiredcompounds of the following structure: ##STR22## Alternatively, toprepare compounds of Formula III, a substituted methacrylate of theformula: ##STR23## wherein L represents a leaving group as previouslydefined, R³⁵ and R³⁶ represent hydrogen and radicals as defined for R¹ ;and R³⁷ represents alkyl, aralkyl, cycloalkyl and cycloalkylalkylradicals, is reacted with a suitable sulfonating agent, such as, forexample, a sulfinic acid represented by the formula R'SO₂ M, wherein R'represents radicals as defined above and M represents a metal adapted toform a salt of the acid, e.g., sodium, to produce the correspondingsulfone represented by the formula: ##STR24## wherein R', R³⁵, R³⁶ andR³⁷ are as defined above. The sulfone is then hydrolyzed in the presenceof a suitable base, such as lithium hydroxide, sodium hydroxide and thelike, to the compound represented by the formula: ##STR25## wherein R',R³⁵ and R³⁶ represent radicals as defined above. The resulting compoundis then asymmetrically hydrogenated utilizing an asymmetrichydrogenation catalyst such as, for example, a ruthenium-BINAP complex,to produce the reduced product, substantially enriched in the moreactive isomer, represented by the formula: ##STR26## wherein R', R³⁵ andR³⁶ represent radicals as defined above. Where the more active isomerhas the R-stereochemistry, a Ru(R-BINAP) asymmetric hydrogenationcatalyst can be utilized. Conversely, where the more active isomer hasthe S-sterochemistry, a Ru(S-BINAP) catalyst can be utilized. Where bothisomers are active, or where it is desired to have a mixture of the twodiastereomers, a hydrogenation catalyst such as platinum, or palladium,on carbon can be utilized to reduce the above compound. The reducedcompound is then coupled to the amino alcohol derivatives, as describedabove, to produce compounds of Formula III.

Preparation of Compounds of Formula IV

To produce compounds of Formula IV, starting with a lactate of theformula: ##STR27## wherein P" represents alkyl radicals, such as, forexample, ethyl, methyl, benzyl and the like. The hydroxyl group of thelactate is protected as its ketal by reaction in a suitable solventsystem with methyl isopropenyl ether (1,2-methoxypropene) in thepresence of a suitable acid. Suitable solvent systems include methylenechloride, tetrahydrofuran and the like as well as mixtures thereof.Suitable acids include POCl₃ and the like. It should be noted thatwell-known groups other than methyl isopropenyl ether can be utilized toform the ketal. The ketal is then reduced with diisobutylaluminumhydride (DIBAL) at -78° C. to produce the corresponding aldehyde whichis then treated with ethylidene triphenylphosphorane (Wittig reaction)to produce a compound represented by the formula: ##STR28##

The ketal protecting group is then removed utilizing procedureswell-known in the art such as by mild acid hydrolysis. The resultingcompound is then esterified with isobutyryl chloride to produce acompound of the formula: ##STR29##

This compound is then treated with lithium diisopropyl amide at -78° C.followed by warming of the reaction mixture to room temperature toeffect a Claisen rearrangement ( 3,3!) to produce the corresponding acidrepresented by the formula: ##STR30##

Treatment of the acid with benzyl bromide in the presence of a tertiaryamine base, e.g., DBU, produces the corresponding ester which is thencleaved oxidatively to give a trisubstituted succinic acid: ##STR31##

The trisubstituted succinic acid is then coupled to the urea isostere asdescribed above. To produce the free acid, the benzyl ester is removedby hydrogenolysis to produce the corresponding acid. The acid can thenbe converted to the primary amide by methods well-known in the art.

An alternative method for preparing trisubstituted succinic acidsinvolves reacting an ester of acetoacetic acid represented by theformula: ##STR32## where R is a suitable protecting group, such asmethyl, ethyl, benzyl or t-butyl with sodium hydride and a hydrocarbylhalide (R³¹ X or R³² X) in a suitable solvent, e.g., THF, to produce thecorresponding disubstituted derivative represented by the formula:##STR33##

This disubstituted acetoacetic acid derivative is then treated withlithium diisopropyl amide at about -10° C. and in the presence ofPhN(triflate)₂ to produce a vinyl triflate of the formula: ##STR34##

The vinyl triflate is then carbonylated utilizing a palladium catalyst,e.g. , Pd₂ (OAc)(Ph₃)P, in the presence of an alcohol (R"OH) or water(R"=H) and a base, e.g., triethylamine, in a suitable solvent such asDMF, to produce the olefinic ester or acid of the formula: ##STR35##

The olefin can then be subsequently asymmetrically hydrogenated, asdescribed above, to produce a trisubstituted succinic acid derivative ofthe formula: ##STR36##

If R" is not H, the ester group can be removed either by hydrolysis,acidolysis, or hydrogenolysis, and the corresponding acid is thencoupled to the amino alcohol derivatives as described above and then,optionally, the R group removed to produce the corresponding acid, andoptionally, converted to the amide.

Alternatively, one can react the amino alcohol derivatives with either asuitably monoprotected succinic acid or glutaric acid of the followingstructure; ##STR37## followed by removal of the protecting group andconversion of the resulting acid to an amide. One can also react ananhydride of the following structure; ##STR38## with the amino alcoholderivatives and then separate any isomers or convert the resulting acidto an amide and then separate any isomers.

it is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the urea derivative or analog thereof, e.g.coupling, to the amino acid PNH(CH₂)_(t) CH(R¹)COOH, carried through aprocedure referred to in the art as reductive amination. Thus, a sodiumcyanoborohydride and an appropriate aldehyde R⁶ C(O)H or ketone R⁶C(O)R⁶ can be reacted with the urea derivative compound or appropriateanalog at room temperature in order to reductively aminate any of thecompounds of Formulas I-VI. It is also contemplated that where R³ of theamino alcohol intermediate is hydrogen, the inhibitor compounds of thepresent invention wherein R³ is an alkyl radical, or other substituentwherein the α-C contains at least one hydrogen, can be prepared throughreductive amination of the final product of the reaction between theamino alcohol and the amine or at any other stage of the synthesis forpreparing the inhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties such as tautomers thereof and compounds wherein one or moreof the various R groups are simple variations of the substituents asdefined therein, e.g., wherein R is a higher alkyl group than thatindicated. In addition, where a substituent is designated as, or can be,a hydrogen, the exact chemical nature of a substituent which is otherthan hydrogen at that position, e.g., a hydrocarbyl radical or ahalogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

Examples 1-45 illustrate compounds wherein X is N rather than O orC(R¹⁷). However, as shown in Examples 46 and 47, the nitrogen can bereplaced as shown in such Examples 46 and 47 by replacing the isocyanateR⁴ NCO with an acid chloride or anhydride where X is C, or with achloroformate or pyrocarbonate where X is O, to produce the compounds ofthe present invention. Furthermore, as shown in Examples 48 and 49, suchcompounds are effective retroviral protease inhibitors. Thus, utilizingthe procedures set forth herein, the compounds shown in Tables 20-46could be prepared.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

EXAMPLE 1 Preparation of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide

Part A:

To a solution of 75.0g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150°-151° C. and M+Li⁺ =340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102°-103°C. and MH⁺ 298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisobutylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN= 3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl!N-(2-methylpropyl)!amine mp 108.0°-109.5° C., MH⁺ m/z=371.

Part D:

A solution of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(2-methylpropyl)amine in 10 ml of tetrahydrofuran was treated withtert-butylisocyanate (267 mg, 2.70 mmol) at room temperature for 5minutes. The solvent was removed in vacuo and replaced with ethylacetate. The ethyl acetate solution was washed with 5% citric acid,water, and brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo to give 1.19 g, 97% of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(2-methylpropyl)!amino-2-(1,1dimethyl)amino!carbonyl!butane, MH⁺m/z-470.

Part E:

A solution of (1.00 g, 2.21 mmol) 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(2-methylpropyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane in 20mL of methanol was hydrogenated over 10% palladium-on-carbon for 4 hoursto give 2(R), 3(S)!-N- 3-amino!-2-hydroxy-4-phenyl!-1-(2-methylpropyl)amino-1-(1,1-dimethylethyl)amino!carbonyl!butane 720 mg,97%.

Part F:

A solution of N-Cbz-L-asparagine (602 mg, 2.26 mmol) andN-hydroxybenzotriazole (493 mg, 3.22 mmol) in 2 mL of dimethylformamidewas cooled to 0° C. and treated with EDC (473 mg, 2.47 mmol). Thesolution was allowed to stir at 0° C. for 20 minutes and then treatedwith 2(R), 3(S)!-N- 3-amino!-2-hydroxy-4-phenyl!-1-(2-methylpropyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane (720mg, 2.15 mmol) in 1 mL of dimethylformamide. The solution was allowed towarm to room temperature and held at this temperature for 7 hours. Thereaction mixture was then poured into 100 mL of 60% saturated aqueoussodium bicarbonate whereupon a white precipitate formed that wasisolated by filtration. The filter cake was washed with water, 5%aqueous citric acid, water and then dried in vacuo to give 1.04 g, 83%of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!, mp.164.0°-166.5° C., MH⁺ m/z=584.

Part G:

A solution of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!butanediamide (1.00 g, 1.72 mmol) in 10 mLof methanol was hydrogenated over 10% palladium-on-carbon for 4 hours togive 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-amino!-butanediamide,784 mg, 99%.

Part H:

A mixture of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-amino!-butanediamide,(784 mg, 1.70 mmol), 2-quinoline carboxylic acid N-hydroxysuccinimideester (459 mg, 1.70 mmol), N-methylmorpholine (343 mg, 3.40 mmol) in 5mL of dichloromethane was stirred an room temperature for 15 minutes.The solvent was removed in vacuo and replaced with ethyl acetate and thesolution washed with 5% aqueous citric acid, saturated aqueous sodiumbicarbonate, brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was recrystallized fromacetone/hexane to give 790 mg, 77% of 1S- 1R*(R*), 2S*!!-N-¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide, mp 107.0°-109.8° C., MH⁺=605.

EXAMPLE 2

The procedure described in Example 1, part C-H, was used to prepare 1S-1R* (R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide.

a) From the reaction of 106 g (3.56 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 6.25 g (71.7 mmol) ofisoamylamine, one obtains 1.27 g (92%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(3-methylbutyl)!amine, mp 130-132 C. and MH* 385. This amine (400 mg,1.04 mmol) was then reacted with tert-butylisocyanate (110 mg, 1.11mmol) to afford 500 mg (100%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(3-methylbutyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane; as anoil, MH⁺ 484.

b) The CBZ protected compound (530 mg, 1.10 mmol) was then deprotectedby hydrogenation over 10% palladium-on-carbon and the resulting freeamine coupled with N-CBZ-L-asparagine (377 mg, 1.42 mmol) in thepresence of N-hydroxybenzotriazole (290 mg, 2.15 mmol) and EDC (300 mg,1.56 mmol) to yield 430 mg (53%) of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!butanediamide, mp 148°-151° C. (dec) andMH⁺ 598. This compound (370 mg, 0.619 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with 2-quinolinecarboxylic acid N-hydroxy-succinimide ester (193mg, 0.714 mmol), in the presence of N-methylmorpholine, to afford 310 mg(70%) of pure 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide; mp 93.5°-95.5° C. and MH⁺619.

EXAMPLE 3

The procedure described in Example 1, part C-H, was used to prepare 1S-1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!2-napthylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide.

a) From the reach ion of 1.80 g (6.05 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 1.15 g (7.31 mmol) of2-(aminomethyl)naphthalene, one obtains 2.11 g (77%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(2-napthylmethyl)!amine, MH⁺ 455. This amine (366.8 mg, 0.807 mmol) wasthen reacted with tert-butylisocyanate (66.4 mg, 0.67 mmol) to afford350.0 mg (94%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(2-napthylmethyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane; asan oil, MH ⁺ 554.

b) The CBZ protected compound (330 mg, 0.596 mmol) was then deprotectedby hydrogenation over 10% palladium-on-carbon and the resulting freeamine coupled with N-CBZ-L-asparagine (165.1 mg, 0.62 mmol) in thepresence of N-hydroxybenzotriazole (142.3 mg, 0.93 mmol) and EDC (130.7mg, 0.68 mmol) to yield 161.7 mg (41%) of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-napthylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!-butanediamide; mp 151°-152° C. (dec) andMH⁺ 668. This compound (91.0 mg, 0.136 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with 2-quinolinecarboxylic acid N-hydroxysuccinimide ester (36.8mg, 0.136 mmol), in the presence of N-methylmorpholine, to afford 65.8mg (70%) of pure 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-napthylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2quinolinylcarbonyl)amino!-butanediamide; mp 119°-120° C. and MH⁺ 689.

EXAMPLE 4

The procedure described in Example 1, part C-H, was used to prepare l S-1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-phenylethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide.

a) From the reaction of 1.00 g (3.36 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 8.19 g (67.0 mmol) of2-phenethyl amine, one obtains 1.10 g (79%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(2-phenylethyl)!amine, mp 137-138 C. and MH⁺ 419. This amine (750 mg,1.79 mmol) was then reacted with tert-butylisocyanate (178 mg, 1.79mmol) to afford 897 mg (97%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(2-phenylethyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane; as anoil, MH⁺ 518.

b) The CBZ protected compound (897 mg, 1.73 mmol) was then deprotectedby hydrogenation over 10% palladium-on-carbon and the resulting freeamine coupled with N-CBZ-L-asparagine (620.7 mg, 2.33 mmol) in thepresence of N-hydroxybenzotriazole (509.5 mg, 3.33 mmol) and EDC (488.0mg, 2.55 mmol) to yield 1.00 g (92%) of 1S- 1R*(R*), 2S*!!-N¹ 3(1,1-dimethylethyl)amino!carbonyl!(2-phenylethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!butanediamide; mp 145 (dec) and MH⁺ 632.This compound (860 mg, 1.36 mmol) was then deprotected by hydrogenationover 10% palladium-on-carbon and the resulting free amine coupled with2-quinolinecarboxylic acid N-hydroxysuccinimide ester (338 mg, 1.25mmol), in the presence of N-methylmorpholine, to afford 450.4 mg (55%)of pure 1S- 1R*(R*), 2S*!!-N¹ 3(1,1-dimethylethyl)amino!carbonyl!(2-phenylethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide; mp 139°-140° C. and MH⁺ 653.

EXAMPLE 5

The procedure described in Example 1, part C-H, was used to prepare 1S-1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2,2-dimethylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide.

a) From the reaction of 1.00 g (3.36 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 7.9 mL (approx. 67 mmol) ofneopentyl amine, one obtains 0.69 g (49%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(2,2-dimethylpropyl)!amine, MH⁺ 385. This amine (686 mg, 1.78 mmol) wasthen reacted with tert-butylisocyanate (180 mg, 1.78 mmol) to afford 860mg (100%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(2,2-dimethylpropyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane;MH⁺ 484.

b) The CBZ protected compound (860 mg, 1.78 mmol) was then deprotectedby hydrogenation over 10% palladium-on-carbon and the resulting freeamine coupled with N-CBZ-L-asparagine (471 mg, 1.77 mmol) in thepresence of N-hydroxybenzotriazole (406 mg, 2.66 mmol) and EDC (374 mg,1.95 mmol) to yield 326 mg (34%) of 1S- R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2,2-dimethylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!-butanediamide; mp 177°-178° C. and MH⁺598. This compound (245 mg, 0.41 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with 2-quinolinecarboxylic acid N-hydroxy-succinimide ester (111mg, 0.41 mmol), in the presence of N-methylmorpholine, to afford 150 mg(59%) of pure 1S- R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2,2-dimethylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide; mp 115°-117° C. and MH⁺ 619.

EXAMPLE 6

The procedure described in Example 1, part C-H, was used to prepare 1S-R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(4-methoxyphenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide;

a) From the reaction of 1.00 g (3.36 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 9.2 g (67 mmol) of4-methoxybenzyl amine, one obtains 1.12 g (76%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(4-methoxyphenylmethyl)!amine, MH⁺ 435. This amine (1.12 g, 2.58 mmol)was then reacted with tert-butylisocyanate (260 mg, 2.58 mmol) to afford1.35 g (98%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(4-methoxyphenylmethyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane;MH⁺ 534.

b) The CBZ protected compound (1.35 g, 2.53 mmol) was then deprotectedby hydrogenation over 10% palladium-on-carbon and the resulting freeamine coupled with N-CBZ-L-asparagine (684 mg, 2.57 mmol) in thepresence of N-hydroxybenzotriazole (590 mg, 3.85 mmol) and EDC (543 mg,2.83 mmol) to yield 442 mg (29%) of 1S- 1R*(R,), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(4-methoxyphenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-phenylmethylcarbamoyl)amino!-butanediamide; mp 175° C. (dec) and MH⁺648. This compound (345 mg, 0.53 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with 2-quinolinecarboxylic acid N-hydroxy-succinimide ester (118mg, 0.44 mmol), in the presence of N-methylmorpholine, to afford 108 mg(31%) of pure 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(4-methoxyphenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide; mp 220° C. (dec) and MLi⁺675.

EXAMPLE 7

The procedure described in Example 1, part C-H, was used to prepare 1S-1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(n-butyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide.

a) From the reaction of 1.48 g (5.0 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 7.314 g (100.0 mmol) ofn-butyl amine, one obtains 1.50 g (80%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-n-butyl)!amine. This amine (1.48 g, 4.0 mmol) was then reacted withtert-butylisocyanate (396 mg, 4.0 mmol) to afford 1.87 g (100%) of 2(R),3(S)!-N- 3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(n-butyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane as an oil.

b) The CBZ protected compound (1.87 g, 4.0 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with N-CBZ-L-asparagine (1.05 g, 3.96 mmol) in the presence ofN-hydroxybenzotriazole (535 mg, 7.9 mmol) and EDC (759 mg, 3.96 mmol) toyield 1.75 g (76%) of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(n-butyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!butanediamide; mp 166°-167° C. and MH⁺ 584.

EXAMPLE 8

The procedure described in Example 1, part C-H, was used to prepare 1S-1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(phenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide.

a) From the reaction of 1.48 g (5.0 mmol) of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and 10.68 g (100.0 mmol) ofbenzyl amine, one obtains 1.88 g (95%) of 2(R), 3(S)!-N-3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenylbutyl!N-(phenylmethyl)!amine. This amine (1.88 g, 4.65 mmol) was then reactedwith tert-butylisocyanate (460.0 mg, 4.6 mmol) to afford 2.24 g (96%) of2(R), 3(S)!-N- 3-(phenylmethylcarbamoyl)amino!-2-hydroxy-4-phenyl!-1-(phenylmethyl)!amino-1-(1,1-dimethylethyl)amino!carbonyl!butane.

b) The CBz protected compound (2.22 g, 4.4 mmol) was then deprotected byhydrogenation over 10% palladium-on-carbon and the resulting free aminecoupled with N-CBZ-L-asparagine (1.17 g, 4.4 mmol) in the presence ofN-hydroxybenzotriazole (1.19 g, 8.8 mmol) and EDC (843 mg, 4.4 mmol) toyield 2.11 g (78%) of 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(phenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(phenylmethylcarbamoyl)amino!butanediamide; mp 156°-158° C. and MH⁺ 618.This compound (1.0 g, 1.62 mmol) was then deprotected by hydrogenationover 10% palladium-on-carbon and the resulting free amine coupled with2-quinolinecarboxylic acid N-hydroxysuccinimide ester (437 mg, 1.62mmol), in the presence of N-methylmorpholine, to afford 640 mg (62%) ofpure 1S- 1R*(R*), 2S*!!-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(phenylmethyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!butanediamide; mp 110.5°-112.5° C. and MH⁺639.

EXAMPLE 9

Additional exemplary compounds are listed in Table 1. These compoundswere prepared according to the following general procedures.

General Procedure for the Preparation of Amino Epoxide.

The amino epoxides can be prepared as shown in Example 1. Alternatively,a protected amino epoxide can be prepared starting with an L-amino acid.

Step A:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) is heated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) isthen slowly added (addition time ˜25 min). The mixture is then stirredat 97° C. for 30 minutes. The solution is cooled to room temperature andextracted with toluene (2×250 ml). The combined organic layers are thenwashed with water, brine, dried over magnesium sulfate, filtered andconcentrated to give an oil product. The crude product is then used inthe next step without purification.

Step B:

The crude benzylated product of the above step is dissolved in toluene(750 ml) and cooled to -55° C. A 1.5M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between -55° to -50° C. (addition time -1 hour). The mixtureis stirred for 20 minutes at -55° C. The reaction is quenched at -55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5N HCl solution (1.8 L) . The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5N NaOH (186 ml) andthen stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with watrand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. AFter 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof matrial can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors are combined and concentrated (34 g). The residue is treatedwith ethyl acetate and hexane which profides an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Step C:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) is cooled to -74° C. A solution of DMSO (12.0 ml, 0.155 mol) indichloromethane (50 ml) is then slowly added at a rate to maintain thetemperature at -74° C. (addition time ˜1.25 hr). The mixture is stirredfor 5 min. followed by addition of a solution of the alcohol (0.074 mol)in 100 ml of dichloromethane (addition time -20 min., temp. -75° C. to-68° C.). The solution is stirred at -78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min. (temp.-78° to -68° C.) upon which the ammonium salt precipitated. The coldmixture is stirred for 30 min. and then water (225 ml) is added. Thedichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than -70° C. has been reported in the literature forthe Swern oxidation. Other Swern modifications and alternatives to theSwern oxidations are also possible.

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to -78° C. A 1.6Msolution of n-butyllithium in hexane (25 ml, 0.040 mol) is then added ata rate to maintain the temperature at -75° C. (addition time -15 min.).After the first addition, additional chloroiodomethane (1.6 ml, 0.022mol) is added again, followed by n-butyllithium (23 ml, 0.037 mol),keeping the temperature at -75° C. The mixture is stirred for 15 min.Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at-75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammoniumchloride solution. The tetrahydrofuran layer isseparated. Theaqueous phase is extracted with ethylacetate (1×300 ml). The combinedorganic layers arewashed with brine, dried over magnesium sulfate,filteredand concentrated to give a brown oil (27.4 g). Theproduct couldbe used in the next step withoutpurification. The desired diastereomercan be purified byrecrystallization at a subsequent step.

Alternately, the product could be purified bychromatography.

General Procedure for the Synthesis of 1,3-Diamino 4-phenylButan-2-olDerivatives.

A mixture of the amine R³ NH₂ (20 equiv.) in dryisopropyl alcohol (20mL/mmol of epoxide to be converted) washeated to reflux and then treatedwith an N-Cbz amino epoxideof the formula: ##STR39## from a solidsaddition funnel over a 10-15 minute period.After the addition iscomplete the solution was maintained atreflux for an additional 15minutes and the progress of thereaction monitored by TLC. In nearly allcases the reactionwas found to be complete after this time period. Thereactionmixture was then concentrated in vacuo to give an oil thatwastreated with n-hexane with rapid stirring whereupon the ringopenedmaterial precipitated from solution. Precipitation wasgenerally completewithin 1 hr and the product was thenisolated by filtration on a Buchnerfunnel and then air dried.The product was further dried in vacuo. Thismethod affordsamino alcohols of sufficient purity for most purposes.

General Procedure for the Reaction of Amino Alcohols withIsocyanates:Preparation of Ureas

A solution from the amino alcohol intetrahydrofuran (THF) was treated atroom temperature with theappropriate isocyanate of formula R⁴ NCO viasyringe undernitrogen. After the reaction has stirred for ˜5 m theprogressof the reaction was monitored by TLC. In nearly all casesthereaction was complete. The solvent was removed in vacuo andtheproduct obtained was of sufficient purity for mostpurposes. The productmay be further purified by dissolutionin ethyl acetate and washing with5% aqueous citric acid,water, and brine. The solvent is dried overanhydrousmagnesium sulfate, filtered and concentrated in vacuo togivethe pure urea.

General Procedure for the Removal of the Protecting GroupsbyHydrogenolysis with Palladium on Carbon

A. Alcohol Solvent

The Cbz-protected peptide derivative was dissolvedin methanol (ca.20mL/mmol) and 10% palladium on carboncatalyst is added under a nitrogenatmosphere. The reactionvessel is sealed and flushed 5 times withnitrogen and then5 times with hydrogen. The pressure is maintained at 50psigfor 1-16 hours and then the hydrogen replaced with nitrogenand thesolution filtered through a pad of celite to removethe catalyst. Thesolvent is removed in vacuo to give thefree amino derivative of suitablepurity to be taken directlyon to the next step.

B. Acetic Acid Solvent

The Cbz-protected peptide derivative was dissolvedin glacial acetic acid(20 mL/mmol) and 10% palladium on carboncatalyst is added under anitrogen atmosphere. The reactionvessel is flushed 5 times with nitrogenand 5 times withhydrogen and then maintained at 40 psig for about 2 h.Thehydrogen was then replaced with nitrogen and the reactionmixturefiltered through a pad of celite to remove thecatalyst. The filtrate wasconcentrated and the resultingproduct taken up in anhydrous ether andevaporated to dryness3 times. The final product, the acetate salt, wasdried invacuo and is of suitable purity for subsequent conversion.

General Procedure for Removal of Boc-protecting Group with4NHydrochloric Acid in Dioxane

The Boc-protected amino acid or peptide is treatedwith a solution of 4NHCl in dioxane with stirring at roomtemperature. Generally thedeprotection reaction is completewithin 15 minutes, the progress of thereaction is monitoredby thin layer chromatography (TLC). Uponcompletion, theexcess dioxane and HCl are removed by evaporation invacuo.The last traces of dioxane and HCl are best removed byevaporationagain from anhydrous ether or acetone. Thehydrochloride salt thusobtained is thoroughly dried in vacuoand is suitable for furtherreaction.

EDC/HOBt Coupling of Cbz-Asparagine (General Procedure)

N-CBZ-(L-asparagine (1.10 eq) andN-hydroxybenzotriazole (HOBt) (1.5 eq)are dissolved in drydimethylformamide (DMF) (2-5 mL/mmol) and cooled inan icebath. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(EDC) (1.10 eq) is added to the stirring solutionand maintained at 0° C.for 10 minutes. A solution of the aminocomponent (free amine), 1.0 eq inDMF (1-2 mL/mmol), is added. In the case of the amine hydrochloride oracetate salt, anequivalent of N-methylmorpholine is also added.! Thereactionmixture is stirred at 0° C. for 1 hour and then atroomtemperature for ˜5-6 hours. The reaction mixture is thenpoured intoa rapidly stirring solution of 60% saturatedaqueous sodium bicarbonate(ca-50 mL/mmol). An immediate whiteprecipitate forms which is collectedon a Buchner funnel andthe solid washed thoroughly with saturatedaqueous sodiumbicarbonate, water, 5% aqueous citric acid solution andwater.The product is thoroughly dried in vacuo and redissolved inDMF,filtered and reprecipitated by the addition to water.The precipitatedproduce is isolated by filtration, washedagain with water and dried invacuo.

General Procedure for Acylation with 2-Quinoline CarboxylicAcidN-Hydroxysuccinimide Ester

A solution of the free amine (or amine acetatesalt) and 1.0 equivalentof N-hydroxysuccinimide 2-quinolinecarboxylate in anhydrousdichloromethane was treated with 1.5 equivalents of N-methyl morpholine(NMM) at room temperature.The progress of the reaction was monitored byTLC and when thereaction was complete the reaction mixture was dilutedwithadditional dichloromethane and the solution washed withsaturatedaqueous sodium bicarbonate, 5% aqueous citric acid,water and brine. Thesolution was dried over anhydrousmagnesium sulfate, filtered andconcentrated in vacuo. Theproduct thus obtained was recrystallized froma mixture ofacetone and hexane.

                                      TABLE 1    __________________________________________________________________________     ##STR40##    Entry No.          R              R.sup.3        R.sup.4    __________________________________________________________________________     1    Cbz.sup.a      CH.sub.3       n-Butyl     2    Cbz            i-Butyl        CH.sub.3     3    Cbz            i-Butyl        n-Butyl     4    Q.sup.b        i-Butyl        n-Butyl     5    Cbz            i-Propyl       n-Butyl     6    Q              i-Propyl       n-Butyl     7    Cbz            C.sub.6 H.sub.5                                        n-Butyl     8    Cbz                          ##STR41##     n-Butyl     9    Cbz                          ##STR42##     n-Butyl    10    Q                          ##STR43##     n-Butyl    11    Cbz                          ##STR44##     n-Butyl    12    Cbz            i-Butyl        n-Propyl    13    Cbz            i-Butyl        CH.sub.2 CH(CH.sub.3).sub.2    14    Cbz                          ##STR45##     n-Butyl    15    Cbz                          ##STR46##     i-Propyl    16    Cbz                          ##STR47##     CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2    17    Cbz            i-Butyl        CH.sub.2 CH.sub.3    18    Cbz            i-Butyl        CH(CH.sub.3).sub.2    19    Cbz            i-Butyl                                         ##STR48##    20    Q              i-Butyl                                         ##STR49##    21    Cbz                          ##STR50##     (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    22    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        CH(CH.sub.3).sub.2    23    Q              i-Butyl        CH(CH.sub.3).sub.2    24    Cbz            i-Butyl        C(CH.sub.3).sub.3    25    Q              i-Butyl        C(CH.sub.3).sub.3    26    Cbz                          ##STR51##     C(CH.sub.3).sub.3    27    Q                          ##STR52##     C(CH.sub.3).sub.3    28    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    29    Q              (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    30    Cbz            CH.sub.2 C6H.sub.5                                        C(CH.sub.3).sub.3    31    Q              CH.sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    32    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    33    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    34    Cbz            n-Butyl        C(CH.sub.3).sub.3    35    Cbz            n-Pentyl       C(CH.sub.3).sub.3    36    Cbz            n-Hexyl        C(CH.sub.3).sub.3    37    Cbz                          ##STR53##     C(CH.sub.3).sub.3    38    Cbz            CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    39    Q              CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    40    Cbz                          ##STR54##     C(CH.sub.3).sub.3    41    Cbz            CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3                                        C(CH.sub.3).sub.3    42    Cbz                          ##STR55##     C(CH.sub.3).sub.3    43    Cbz                          ##STR56##     C(CH.sub.3).sub.3    44    Cbz            (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    45    Q              (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    46    Cbz            (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    47    Q              (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    48    Q                          ##STR57##     C(CH.sub.3).sub.3    49    Q                          ##STR58##     C(CH.sub.3).sub.3    50           ##STR59##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    51           ##STR60##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    52           ##STR61##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    53           ##STR62##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    54           ##STR63##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    55           ##STR64##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    56           ##STR65##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    57           ##STR66##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    58           ##STR67##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    59           ##STR68##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    60           ##STR69##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    61           ##STR70##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    62           ##STR71##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    63           ##STR72##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    64           ##STR73##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    65           ##STR74##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    66           ##STR75##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    67           ##STR76##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    68           ##STR77##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    69           ##STR78##     CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    __________________________________________________________________________     .sup.a benzyloxycarbonyl     .sup.b 2quinolinylcarbonyl

EXAMPLE 10

Following the generalized procedures set forth inExample 9, thecompounds set forth in Table 2 were

                                      TABLE 2    __________________________________________________________________________     ##STR79##    Entry         A                   R.sup.3    R.sup.4    __________________________________________________________________________     1   CbzVal              i-amyl     tBu     2   CbzLeu              i-amyl     t-Bu     3   CbzIle              i-amyl     t-Bu     4   AcD-homo-Phe        i-Bu       n-Bu     5   QuiOrn(γ-Cbz)                              ##STR80## t-Bu     6   CbzAsn              CH.sub.2 CHCH.sub.2                                        t-Bu     7   Acetyl-t-BuGly      i-amyl     t-Bu     8   Acetyl-Phe          i-amyl     t-Bu     9   Acetyl-Ile          i-amyl     t-Bu    10   Acetyl-Leu          i-amyl     t-Bu    11   Acetyl-His          i-amyl     t-Bu    12   Acetyl-Thr          i-amyl     t-Bu    13   Acetyl-NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    14   CbzAsn              i-amyl     t-Bu    15   CbzAla              i-amyl     t-Bu    16   CbzAla              i-amyl     t-Bu    17   Cbz-beta-cyanoAla   i-amyl     t-Bu    18   Cbz-t-BuGly         i-amyl     t-Bu    19   Q-t-BuGly           i-amyl     t-Bu    20   QSCH.sub.3 Cys      i-amyl     t-Bu    21   CbzSCH.sub.3 Cys    i-amyl     t-Bu    22   QAsp                i-amyl     t-Bu    23   Cbz(NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    24   CbzEtGly            i-amyl     t-Bu    25   CbzPrGly            i-amyl     t-Bu    26   CbzThr              i-amyl     t-Bu    27   QPhe                i-amyl     t-Bu    28   CbzPhe              i-amyl     t-Bu    29   Cbz NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    30   Q NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    __________________________________________________________________________

EXAMPLE 11

Following the generalized procedure of Example 9, the compounds listedin Table 3 were

                  TABLE 3    ______________________________________     ##STR81##    Entry            R.sup.1    ______________________________________    1                CH.sub.2 SO.sub.2 CH.sub.3    2                (R)CH(OH)CH.sub.3    3                CH(CH.sub.3).sub.2    4                (R,S)CH.sub.2 SOCH.sub.3    5                CH.sub.2 SO.sub.2 NH.sub.2    6                CH.sub.2 SCH.sub.3    7                CH.sub.2 CH(CH.sub.3).sub.2    8                CH.sub.2 CH.sub.2 C(O)NH.sub.2    9                (S)CH(OH)CH.sub.3    10               CH.sub.2 CCH    11               CH.sub.2 CCH.sub.2    ______________________________________

EXAMPLE 12

Following the generalized procedures of Example 9,the compounds setforth in Table 4 were

                  TABLE 4    ______________________________________     ##STR82##    Entry    R.sup.2        A    ______________________________________     1       n-Bu           CbzAsn     2       cyclohexylmethyl                            CbzAsn     3       n-Bu           Boc     4       n-Bu           Cbz     5       C.sub.6 H.sub.5 CH.sub.2                            Boc     6       C.sub.6 H.sub.5 CH.sub.2                            Cbz     7       C.sub.6 H.sub.5 CH.sub.2                            benzoyl     8       cyclohexylmethyl                            Cbz     9       n-Bu           QAsn    10       cyclohexylmethyl                            QAsn    11       C.sub.6 H.sub.5 CH.sub.2                            CbzIle    12       C.sub.6 H.sub.5 CH.sub.2                            QIle    13       C.sub.6 H.sub.5 CH.sub.2                            Cbz-t-BuGly    14       C.sub.6 H.sub.5 CH.sub.2                            Q-t-BuGly    15       C.sub.6 H.sub.5 CH.sub.2                            CbzVal    16       C.sub.6 H.sub.5 CH.sub.2                            QVal    17       2-naphthylmethyl                            CbzAsn    18       2-naphthylmethyl                            QAsn    19       2-naphthylmethyl                            Cbz    20       n-Bu           CbzVal    21       n-Bu           QVal    22       n-Bu           QIle    23       n-Bu           Cbz-t-BuGly    24       n-Bu           Q-t-BuGly    25       p-F(C.sub.6 H.sub.4)CH.sub.2                            QAsn    26       p-F(C.sub.6 H.sub.4)CH.sub.2                            Cbz    27       p-F(C.sub.6 H.sub.4)CH.sub.2                            CbzAsn    28       C.sub.6 H.sub.5 CH.sub.2                            Cbz-propargylglycine    29       C.sub.6 H.sub.5 CH.sub.2                            Q-propargylglycine    30       C.sub.6 H.sub.5 CH.sub.2                            acetyl-proparglyglycine    31       i-Bu           CbzAsn    ______________________________________

EXAMPLE 13

The compounds listed in Table 5 were preparedaccording to thegeneralized procedures of Example

                  TABLE 5    ______________________________________     ##STR83##    Entry      X(H)R.sup.4       A    ______________________________________    1          NH.sup.t Bu       CbzAsn    2          NEt.sub.2         Cbz    3          NHC(CH.sub.3).sub.2 CH.sub.2 CH.sub.3                                 Cbz    ______________________________________

EXAMPLE 14

The compounds of Table 6 were prepared accordingto the generalizedprocedures set forth in Example 9 exceptthat instead of an isocyanate,an isothiocyanate equivalentwas

                  TABLE 6    ______________________________________     ##STR84##    Entry                XHR.sup.4    ______________________________________    1                    NHEt    2                    NH.sup.t Bu    ______________________________________

The Cbz group of the compounds shown in Examples 13 and 14 can beremoved as described in Example 9 and the resultingcompound can becoupled to a desired α- or β-amino acid orthe like to produce compoundsof the present invention.

EXAMPLE 15

The compounds shown in Table 7 were preparedaccording to the followinggeneral procedure.This general procedure represents a CurtiusRearrangement andreaction with the amino alcohol derivative aspreparedfollowing the general procedure in Example 9.

To a solution of 1 mmol of carboxylic acid in12 mL of toluene and 3 mmolof triethylamine at 90° C. under anitrogen atmosphere, was added 1 mmolof diphenylphosphorylazide. After 1 hour, a solution of 1 mmol of aminoalcoholderivative in 3.5 mL of either N,N-dimethylformamide ortoluenewas added. After 1 hour, the solvent was removedunder reduced pressure,ethyl acetate and water added and thelayers separated. The organic layerwas washed with 5%citric acid, sodium bicarbonate, brine, dried,filtered andconcentrated to afford the crude product. This wasthenrecrystallized or chromatographed on silica gel to affordthepurified final

                  TABLE 7    ______________________________________     ##STR85##    R.sup.3          R.sup.4    ______________________________________    CH.sub.2 CH(CH.sub.3).sub.2                     C(CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR86##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR87##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR88##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR89##    ______________________________________

EXAMPLE 16

A. Preparation of 4(4-methoxybenzyl)itaconate ##STR90##

A 5 L three-necked round bottomed flask equippedwith constant pressureaddition funnel, reflux condenser,nitrogen inlet, and mechanical stirrerwas charged withitaconic anhydride (660.8 g, 5.88 mol) and toluene (2300mL).The solution was warmed to reflux and treated with4-methoxybenzylalcohol (812.4 g, 5.88 mol) dropwise over a2.6 h period. The solutionwas maintained at reflux for anadditional 1.5 h and then the contentswere poured into three2 L erlenmeyer flasks to crystallize. The solutionwasallowed to cool to room temperature whereupon the desiredmono-estercrystallized. The product was isolated byfiltration on a Buchner funneland air dried to give 850.2 g,58% of material with mp 83°-85° C., asecond crop, 17% wasisolated after cooling of the filtrate in an icebath. ¹ HNMR (CDCl₃) 300 MHz 7.32(d, J=8.7 Hz, 2H), 6.91(d, J=8.7Hz,2H), 6.49(s, 1H), 5.85(s, 1H), 5.12(s, 2H), 3.83(s, 3H),3.40 (s, 2H).

B. Preparation of Methyl 4(4-methoxybenzyl)itaconate ##STR91##

A 5 L three-necked round bottomed flask equippedwith reflux condenser,nitrogen inlet, constant pressureaddition funnel and mechanical stirrerwas charged with 4(4-methoxybenzyl)itaconate(453.4 g, 1.81 mol) andtreated with1,5-diazabicyclo 4.3.0!non-5-ene (275.6 g, 1.81 mol),(DBU),dropwise so that the temperature did not rise above 15° C.To thisstirring mixture was added a solution of methyliodide (256.9 g, 1.81mol) in 250 mL of toluene from thedropping funnel over a 45 m period.The solution was allowedto warm to room temperature and stirred for anadditional3.25 h.

The precipitated DBU hydroiodide was removed byfiltration, washed withtoluene and the filtrate poured intoa separatory funnel. The solutionwas washed with sat. aq.NaHCO₃ (2×500 mL), 0.2N HCl (1×500 mL), andbrine (2×500 mL), dried over anhyd. MgSO₄, filtered, and thesolventremoved in vacuo. This gave a clear colorless oil, 450.2 g,94%whose NMR was consistent with the assigned structure.¹ H NMR (CDCl₃) 300MHz 7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H), 6.34(s, 1H), 5.71(s,1H), 5.09(s, 2H), 3.82(s, 3H),3.73(s, 3H), 3.38(s, 2H). ¹³ C NMR (CDCl₃)170.46, 166.47,159.51, 133.55, 129.97, 128.45, 127.72, 113.77,66.36,55.12, 51.94, 37.64.

C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)methylsuccinate##STR92##

A 500 mL Fisher-Porter bottle was charged withmethyl4(4-methoxybenzyl)itaconate (71.1 g, 0.269 mol),rhodium (R,R) DiPANPcatalyst (204 mg, 0.269 mmol, 0.1 mol %)and degassed methanol (215 mL).The bottle was flushed 5 times with nitrogen and 5 times with hydrogento a finalpressure of 40 psig. The hydrogenation commencedimmediatelyand after ca. 1 h the uptake began to taper off,after 3 h the hydrogenuptake ceased and the bottle wasflushed with nitrogen, opened and thecontents concentratedon a rotary evaporator to give a brown oil that wastaken upin boiling iso-octane (ca. 200 mL, this was repeatedtwice),filtered through a pad of celite and the filtrateconcentrated invacuo to give 66.6 g, 93% of a clearcolorless oil, ¹ H NMR (CDCl₃ 300MHz 7.30(d, J=8.7 Hz, 2H),6.91 (d, J=8.7 Hz, 2H), 5.08 (s, 2H), 3.82(s,3H), 3.67 (s,3H), 2.95(ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1,16.5 Hz, 1H), 2.45(dd, J=5.7, 16.5 Hz, 1H), 1.23(d, J=7.5 Hz,3H).

D. Preparation of Methyl 2(R)-methylsuccinate

A 3 L three-necked round-bottomed flask equippedwith a nitrogen inlet,mechanical stirrer, reflux condenserand constant pressure additionfunnel was charged withmethyl 4(4-methoxybenzyl) 2(R)-methylsuccinate(432.6 g, 1.65 mol) and toluene (1200 mL). The stirrer was started andthesolution treated with trifluoroacetic acid (600 mL) from thedroppingfunnel over 0.25 h. The solution turned a deeppurple color and theinternal temperature rose to 45° C.After stirring for 2.25 h thetemperature was 27° C. and thesolution had acquired a pink color. Thesolution wasconcentrated on a rotary evaporator. The residue wasdilutedwith water (2200 mL) and sat. aq. NaHCO₃ (1000 mL).Additional NaHCO₃ wasadded until the acid had beenneutralized. The aqueous phase wasextracted with ethylacetate (2×1000 mL) to remove the by-products andtheaqueous layer was acidified to pH=1.8 with conc. HCl. Thissolutionwas extracted with ethyl acetate (4×1000 mL),washed with brine, driedover anhyd. MgSO₄, filtered andconcentrated on a rotary evaporator togive a colorlessliquid 251 g, >100% that was vacuum distilled through ashortpath apparatus cut 1: bath temperature 120° C. @ >1 mm, bp25°-29°C.; cut 2: bath temperature 140° C. @ 0.5 mm, bp 95°-108° C.,151 g,!_(D) @ 25° C.=+1.38° C.(c=15.475, MeOH), α!_(D) =+8.48° C.(neat); cut3: bath temperature 140° C., bp 108° C., 36 g, α!_(D) @ 25° C.=+1.49°C.(c=15.00, MeOH), α!_(D) =+8.98° C. (neat). Cuts 2 and 3 were combinedto give 189 g, 78% of product, ¹ H NMR(CDCl₃) 300 MHz 11.6(brs, 1H),3.72(s, 3H), 2.92(ddq, J=5.7,6.9, 8.0 Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz,1H), 2.47(dd,J=5.7, 16.8 Hz, 1H), 1.26(d, J=6.9 Hz, 3H).

E. Preparation of Methyl Itaconate ##STR93##

A 50 mL round bottomed flask equipped with refluxcondenser, nitrogeninlet and magnetic stir bar was chargedwith methyl4(4-methoxybenzyl)itaconate (4.00 g, 16 mmol).The solution was kept atroom temperature for 18 hours andthen the volatiles were removed invacuo. The residue wastaken up in ethyl acetate and extracted threetimes withsaturated aqueous sodium bicarbonate solution. Thecombinedaqueous extract was acidified to pH=1 with aqueouspotassiumbisulfate and then extracted three times with ethyl acetate.Thecombined ethyl acetate solution was washed withsaturated aqueous sodiumchloride, dried over anhydrousmagnesium sulfate, filtered, andconcentrated in vacuo. Theresidue was then vacuum distilled to give 1.23g, 75% of pureproduct, bp 85-87 @ 0.1 mm. ¹ H NMR (CDCl₃) 300 MHz6.34(s,1H), 5.73(s, 2H), 3.76(s, 3H), 3.38(s, 2H). ¹³ C NMR(CDCl₃)177.03, 166.65, 129.220, 132.99, 52.27, 37.46.

F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate:Preparation ofMethyl N-Moz-α-methyl β-alanine. ##STR94##

A 5L four necked round bottomed flask equippedwith a nitrogen inlet,reflux condenser, mechanical stirrer,constant pressure addition funnel,and thermometer adapterwas charged with methyl 2(R)-methyl succinate(184.1 g, 1.26 mol), triethylamine (165.6 g, 218 mL, 1.64 mol, 1.3equivalents), and toluene (1063 mL). The solution waswarmed to 85° C.and then treated dropwise with a solution ofdiphenylphosphoryl azide(346.8 g, 1.26 mol) over a period of1.2 h. The solution was maintainedat that temperature foran additional 1.0 h and then the mixture wastreated with4-methoxybenzyl alcohol (174.1 g, 1.26 mol) over a 0.33hperiod from the dropping funnel. The solution was stirredat 88° C. foran additional 2.25 h and then cooled to roomtemperature. The contents ofthe flask were poured into aseparatory funnel and washed with sat. aq.NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL), brine (1×500 mL), driedoveranhyd. MgSO₄, filtered, and concentrated in vacuo to give302.3 g,85% of the desired product as a slightly brown oil.₁ H NMR (CDCl₃) 300MHz 7.32(d, J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz, 2H), 5.2(brm, 1H), 5.05 (s,2H), 3.83(s, 3H), 3.70 (s,H), 3.35(m, 2H), 2.70(m, 2H), 1.20(d, J=7.2Hz, 3H).

G. Hydrolysis of Methyl N-Moz-α-methyl β-alanine:Preparation of α-methylβ-alanine Hydrochloride ##STR95##

A 5 L three-necked round bottomed flask equippedwith a reflux condenser,nitrogen inlet and mechanicalstirrer was charged with methylN-Moz-α-methyl β-alanine(218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12Nhydrochloric acid (1960 mL). The solution was then heatedtoreflux for 3 h. After the solution had cooled to roomtemperature (ca. 1h) the aqueous phase was decanted fromorganic residue (polymer) and theaqueous phase concentratedon a rotary evaporator. Upon addition ofacetone to theconcentrated residue a slightly yellow solid formed thatwasslurried with acetone and the white solid was isolated byfiltrationon a Buchner funnel. The last traces of acetonewere removed byevacuation to give 97.7 g, 90% of pureproduct, mp 128.5°-130.5° C.α!_(D) @ 25° C.=9.0° (c=2.535,Methanol). ¹ H NMR (D₂ O) 300 MHz 3.29(dd,J=8.6, 13.0 Hz,1H), 3.16(dd, J=5 0, 13.0 m Hz, 1H), 2.94(ddq, J=7.2,5.0,8.6 Hz, 1H), 1.30(d,J=7.2 Hz, 3H); ¹³ C NMR (D₂ O) 180.84,44.56,40.27, 17.49.

H. Preparation of N-Boc α-Methyl β-Alanine ##STR96##

A solution of α-methyl β-alanine hydrochloride(97.7 g, 0.70 mol) inwater (1050 mL) and dioxane (1050 mL)the pH was adjusted to 8.9 with2.9N NaOH solution. Thisstirring solution was then treated withdi-tert-butylpyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) allatonce. The pH of the solution was maintained between 8.7 and9.0 by theperiodic addition of 2.5N NaOH solution. After2.5 h the pH hadstabilized and the reaction was judged to becomplete. The solution wasconcentrated on a rotaryevaporator (the temperature was maintained at<40° C.). Theexcess di-tert-butyl pyrocarbonate was removed byextractionwith dichloromethane and then the aqueous solutionwasacidified with cold 1N HCl and immediately extracted withethylacetate (4×1000 mL). The combined ethyl acetateextract was washed withbrine, dried over anhyd. MgSO₄,filtered and concentrated on a rotaryevaporator to give athick oil 127.3 g, 90% crude yield that was stirredwithn-hexane whereupon crystals of pure product formed, 95.65 g,67%, mp76°-78 ° C., α!_(D) @ 25° C.=-11.8° (c=2.4, EtOH) A secondcrop wasobtained by concentration of the filtrate anddilution with hexane, 15.4g, for a combined yield of 111.05 g,78%. ¹ H NMR (acetone D₆) 300 MHz11.7 (brs, 1H), 6.05 (brs1H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50 (m, 1H),1.45(s, 9H),1.19 (d, J=7.3 Hz, 3H); ¹³ C NMR (acetone D₆) 177.01,79.28,44.44, 40.92, 29.08, 15.50. Elemental analysis calc'd. forC₉ H₁₇NO₄ : C, 53.19, H, 8.42; N, 6.89. Found: C, 53.36; H,8.46; N, 6.99.

I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

A solution of N-4-Methoxybenzyloxycarbonylα-methyl β-alanine methylester (2.81 g, 10.0 mmol) in 30 mLof 25% aqueous methanol was treatedwith lithium hydroxide(1.3 equivalents) at room temperature for a periodof 2 h.The solution was concentrated in vacuo and the residue takenup ina mixture of water and ether and the phases separatedand the organicphase discarded. The aqueous phase wasacidified with aqueous potassiumhydrogen sulfate to pH=1.5 and then extracted three times with ether.The combinedethereal phase was washed with saturated aqueoussodiumchloride solution, dried over anhydrous magnesium sulfate,filteredand concentrated in vacuo co give 2.60 g, 97%ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA)which waspurified by recrystallization from a mixture ofethyl acetate and hexaneto give 2.44 g, 91% of pure product,mp 96°-97° C., MH+=268. ¹ H NMR (D₆-acetone/300 MHz) 1.16 (3H, d,J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, s), 4.99 (2H,s), 6.92(2H, 4, J=8.7 Hz), 7.13(2H, d, J=8.7 Hz).

J. Preparation of Propanamide, 3-(4-methoxybenzyloxycarbonyl)-N- 3-(1,1-dimethylethyl)amine!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-IS- IR*(S*),2S*!!-

N-Moz-AMBA (468 mg, 1.75 nmmol) was dissolved in 5 mLof DMF, HOBT (355mg, 2.6 mmol) was added and the solution wascooled to 0° C. The solutionwas treated with (336 mg,1.75 mmol) EDC for 15 minutes. To this wasadded(612 mg, 1.75 mmol) of 2R, 3S3-amino-1-isoamyl-1-(t-butylcarbonyl)amino4-phenyl-2-butanol in 10 mL ofDMF andreaction stirred for 16 hours at room temperature. The DMFwasconcentrated to 5 mL and the product was precipitated byaddition to 60%saturated aqueous NaHCO₃. The solid wastaken up in ethyl acetate andwashed with KHSO₄, NaHCO₃,NaCl (saturated), dried over MgSO₄ andconcentrated to yield680 mg of crude product which was crystallized fromCH₂ Cl₂,Et₂ O, hexane, to yield 300 mg of pure product.

EXAMPLE 17

The compounds of Table 8 were prepared accordingto the procedure listedbelow and that utilized in Example16.

Propaneamide, 3- (1,1-dimethylethyl)butoxycarbonyl!amino-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-,1S- 1R*(S*),2S*!- (Table 8, Entry 11)

Part A:

A solution of N-t-butyloxycarbonyl-2-(R)-methyl-3-aminopropionicacid(372 mg, 1.83 mmol) and N-hydroxybenzotriazole(371 mg, 2.75 mmol) in 5mL ofdimethylformamide was cooled to 0° C. To this was added EDC(351 mg,1.83 mmol) and the solution was stirred for 15 minutes. To this chilledsolution was added a solution of3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2(R)-hydroxy-1(S)(phenylmethyl)propylaminein 5 mL ofdimethylformamide and stirred for 15 hours.Thedimethylformamide was removed and replaced with 50 mL ofethylacetate, and the organic phase was extracted with 5%potassium hydrogensulfate, saturated sodium bicarbonate andbrine. The ethyl acetate layerwas dried over magnesiumsulfate, filtered and concentrated to yield 613mg ofproduct after recrystallization from ethyl acetate,hexanes. (63%yield). M+Li 541

Part B:

Preparation of Propaneamide, 3-amino-N- 3-(1,1-dimethylethyl)amino!carbonyl!-(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-,1S- 1R*(S*),2S*!-hydrochloride

The product from part A. (577 mg, 1.08 mmol) wasdissolved in 40 mL of 4NHCl in dioxane and the solutionstirred for 2 hours, and concentrated toyield thehydrochloride salt in quantitative yield.

Part C:

Preparation of Propaneamide, 3-(2-methylpropanoylamino)-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-,1S- 1R*(S*),2S*!-

The product from part B. (236 mg, 0.5 mmol) wasdissolved in anhydroustetrahydrofuran and to this was addedN-methylmorpholine (160 mg, 1.5mmol) upon which time aprecipitate formed. To this suspension was addedisobutyrylchloride (53.5 mg, 0.5 mmol) and the suspension stirred for15hours. The suspension was diluted with ethyl acetate andwashed with 5%potassium hydrogen sulfate, saturated sodiumbicarbonate and brine. theorganic layer was dried overmagnesium sulfate, filtered and concentratedto yield 195 mgof crude product which was chromatographed on silicagelwith 5% methanol methylene chloride to yield 121.5 mg (50%yield) ofpure product. M+Li 511

                                      TABLE 8    __________________________________________________________________________     ##STR97##    Entry        R                        R.sub.1    __________________________________________________________________________         ##STR98##               CH.sub.3    2         ##STR99##               CH.sub.3    3         ##STR100##              CH(CH.sub.3).sub.2    4         ##STR101##              CH(CH.sub.3).sub.2    5         ##STR102##              C(CH.sub.3).sub.3    6         ##STR103##              CH.sub.3    7         ##STR104##              CH.sub.3    8         ##STR105##              CH.sub.3    9         ##STR106##              CH.sub.3    10         ##STR107##              CH.sub.3    11         ##STR108##              CH.sub.3    12         ##STR109##              CH.sub.3    13         ##STR110##              CH.sub.3    14         ##STR111##              CH.sub.3    15         ##STR112##    16         ##STR113##    __________________________________________________________________________

EXAMPLE 18

Following generally the procedure set forth inExample 16, the compoundsshown in Table 9 were

                  TABLE 9    ______________________________________     ##STR114##    R.sup.1         R.sup.1'                 R.sup.1"  R    ______________________________________    H    H       H                            ##STR115##    H    H       H                            ##STR116##    H    CH.sub.3                 H                            ##STR117##    H    CH.sub.3                 CH.sub.3                            ##STR118##    H    H       CO.sub.2 CH.sub.3                            ##STR119##    H    H       H                            ##STR120##    H    H       H                            ##STR121##    H    H       CONH.sub.2                           Cbz    H    H       CONH.sub.2                           2-quinolinylcarbonyl    ______________________________________

EXAMPLE 19

The procedure set forth below in Example 23 wasgenerally utilized toprepare the compounds shown in

                  TABLE 10    ______________________________________     ##STR122##    R                 R'          X    ______________________________________    R = H             R' = H      X = H    R = Me            R' = Me     X = H    R = H             R' = Me     X = H    R = Me            R' = Me     X = F    R = H             R' = Me     X = F    R = Cbz           R' = Me     X = H    R = H             R' = Bz     X = H    R + R' = pyrrole*             X = H    ______________________________________     *lle in place of tbutylglycine

EXAMPLE 20

This example illustrates preparation ofcompounds wherein R⁴ and R⁵together with N, forms aheterocycloalkyl radical.

a) Pyrrolidine carbamoyl chloride. ##STR123##

A slitting solution of triphosgene (27.78 g, 0.103 mol) in 40 mL toluenewas cooled to -20 ° C. in an ice/saltbath under a blanket of nitrogenand treated with a solutionof N-methylmorpholine (27.3 g, 0.27 mol) in20 mL of toluenedropwise over 1 h. This solution was then treated withasolution of pyrrolidine (19.8 g, 0.27 mol) in 30 mL oftoluene over aperiod of 30 m. The solution was allowed towarm to room temperature,filtered and the filtrateconcentrated in vacuo to give an oil that waspurified byvacuum distillation through a 12" Vigeraux column to give20.7g, 56%, bp 58 ° C. @ 0.6 mm, of pure product.

b) Butanediamide, N¹ 3-(4-fluorophenyl)methyl)!(1-pyrrolidinylcarbonyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!- 1S 1R*(R*), 2S*!!- ##STR124##

A stirring solution of 1S- 1R*(R*), 2S*!!-N¹ - 3-(4-fluorophenyl)methyl!amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)aminobutanediamide(1.08 g, 1.91 mmol) (prepared asin Example31) in 7 mL of anhydrous DMF was treated withpyrrolidinecarbamoyl chloride (2 60 mg, 1.95mmol),4-dimethylaminopyridine (15 mg), and N-methylmorpholine (380 mg,3.76 mmol). The solution was stirred at roomtemperature for 3 h and thenconcentrated in vacuo to give asemi-solid that was dissolved inmethanol/water ca. 2:1. Asolid formed from this solid that was isolatedby filtrationon a Buchner funnel and washed with water, 5% aq.citricacid and water and air dried to give 130 mg, 11% of pureproduct,TLC on SiO₂ eluting with 7% methanol in ethylacetate showed one spotwith R_(f) =0.64.

c) Butanediamide, N¹ 3-(4-fluorophenyl)methyl)!(4-morpholinylcarbonyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!- 1S 1R*(R*), 2S*!!- ##STR125##

To a stirring solution of 1S- 1R*(R*),2S*!!-N¹ - 3-(4-fluorophenyl)methyl!amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)aminobutanediamide(520 mg, 0,922 mmol),triethylamine (172 mg,1.70 mmol), 4-dimethylaminopyridine (50 mg), andmorpholinocarbamoyl chloride (157.3 mg, 1.05 mmol) in 5 mL ofchloroform.The initially heterogeneous mixture was heatedto reflux for 6 h. Thesolution was then diluted withadditional chloroform, poured into aseparatory funnel andwashed with 1N KHSO₄, sat. aq. NaHCO₃, dried overanhyd.MgSO₄, filtered, and concentrated in vacuo to give a whitesolidthat was purified by column chromatography on SiO₂ eluting withethanol/ethyl acetate to give 380 mg, 61%, ofpure product.

EXAMPLE 21

This example illustrates preparation of compoundswherein R⁴ and R⁵ areboth other than H.

Butanediamide, N¹ 3-(diethylamino)carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!- 1S- 1R* (R*),2S*!!- ##STR126##

To a stirring solution of 1S- 1R*(R*),2S*!!-N¹ -3-(methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino-butane diamide!(119 mg, 0.21 mmol)triethylamine (59 mg, 0.58 mmol), 4-dimethylaminopyridine(9 mg), anddiethyl carbamoyl chloride (157.3 mg,1.05 mmol) in 4 mL of chloroform.The mixture was kept atroom temperature for 26 h. The solution was thendilutedwith additional chloroform, poured into a separatory funnelandwashed with 1N KHSO₄, sat. aq. NaHCO₃, dried over anhyd.MgSO₄, filtered,and concentrated in vacuo to give a whitesolid that was purified bycolumn chromatography on SiO₂ eluting with methanol/CH₂ Cl₂ to give 20mg, 15%, of pureproduct.

EXAMPLE 22

Following the procedures set forth in Examples 20 and 21, the compoundslisted in Table 11 were

                  TABLE 11    ______________________________________     ##STR127##     ##STR128##                        ##STR129##    CH.sub.2 CH(CH.sub.3).sub.2                       N(CH.sub.3).sub.2    CH.sub.2 CH(CH.sub.3).sub.2                       N(CH.sub.2 CH.sub.3).sub.2    CH.sub.2 CH(CH.sub.3).sub.2                       N(CH(CH.sub.3).sub.2).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                       N(CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                       N(CH.sub.2 CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                        ##STR130##     ##STR131##        N(CH.sub.3).sub.2     ##STR132##        N(CH.sub.2 CH.sub.3).sub.2     ##STR133##                        ##STR134##     ##STR135##                        ##STR136##     ##STR137##        N(CH.sub.3) (t-Bu)     ##STR138##                        ##STR139##     ##STR140##                        ##STR141##     ##STR142##                        ##STR143##     ##STR144##                        ##STR145##     ##STR146##                        ##STR147##     ##STR148##                        ##STR149##     ##STR150##                        ##STR151##     ##STR152##                        ##STR153##    ______________________________________

EXAMPLE 23 3-(1,1-dimethylethyl)amino!carbonyl(3-methylbutyl)amino-2(R)-hydroxy-1(S)-(phenylmethyl!propylamine

This example illustrates preparation of compoundswherein R¹ is an alkylgroup other than an alkyl group of anaturally occurring amino acid sidechain.

Part A:

3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino-2(R)-hydroxy-1(S)-N-(benzyloxycarbonyl)(phenylmethyl()propyl amine! (4.7 gm, c 9.7 mmol)was combined with 10% Pd on carbon (200 mg) and conc.HCl (3 mL) inethanol (35 mL) and hydrogenated at 50 psi ofhydrogen for 2.5 h. Thereaction mixture was filtered throughdiatomaceous earth and concentratedon a rotary evaporator toa yellow hygroscopic solid; 3.7 gm, 100%.

Part B:

Butaneamide, 2-(phenylmethyloxycarbonyl)amino!-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl-3,3-dimethyl-1S-1R*(R*),25*!!-

N-Cbz-L-tert-leucine (172 mg, 0.65 mmol) andN-hydroxybenzotriazole (100mg, 0.65 mmol) in DMF (3 mL) wascooled to 0° C. and EDC (115 mg, 0.60mmol) added. After 45 min the amine from Part A (193 mg, 0.50 mmol)andN-methylmorpholine (60 uL, 0.55 mmol) were added. Thereaction wasstirred at ambient temperature for 18 h andpoured into a solution of 50%saturated NaHCO₃ (25 mL). Thesolid was collected by suction filtration,washed with waterand dried in-vacuo. The solid was chromatographed onSiO₂ using 2% MeOH in CH₂ Cl₂. The appropriate fractions werepooled andconcentrated to afford a white solid; 220 mg,MH⁺ 597, TLC (SiO₂ 2%MeOH/CH₂ Cl₂) R_(f) =0.2. CHN requires:C, 68.42, H, 8.78, N, 9.39;found: C, 68.03, H, 8.83, N,9.33.

Part C:

Butaneamide, 2-amino-N- -3-1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino)-2-hydroxy-1-(phenylmethylpropyl!-3,3-dimethyl-,1S- 1R*(R*),2S*!-

The product from Part B (570 mg, 0.95 mmol) and 4%Pd on carbon (150 mg)in ethanol (30 mL) was hydrogenated at5 psi for 2.75 h. The reactionmixture was filtered throughdiatomaceous earth and concentrated on arotary evaporatorto an oil; 438 mg, 100%.

Part D:

Butaneamide, 2-(acetylamino)-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-3,3-dimethyl-,1S- 1R*(R*),2S*!-

The product from Part C (206 mg, 0.41 mmol) andN-methylmorpholine (45uL, 0.41 mmol) were dissolved inCH₂ Cl₂ (2.5 mL) and cooled to 0 C.Acetic anhydride (39 uL,0.41 mmol) was then added and the reactionstirred 30 min at0 C., then allowed to warm to ambient temperature andstirfor 30 min. The solvent was removed on a rotary evaporatorand theresidue dissolved in ethanol (2 mL). The ethanolicsolution was slowlypoured into 50% saturated NaHCO₃ (20 mL) and stirred vigorously. Thesolid was collected bysuction filtration and washed with water, 5%citric acid,and again with water; 157 mg, 75%. CHN/1.5 H₂ O requires:C63.24, H, 9.67, N, 10.54; found:C, 63.40, H, 9,41, N, 10.39.

Butaneamide, 2-amino-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-3,3-dimethyl-,1S- 1R*(R*),2S*!-was also capped with the acyl groups shown in Table 12utilizing generally the procedure set forth

                  TABLE 12    ______________________________________    Acyl Group (R)    ______________________________________    benzyloxycarbonyl    tert-butoxycarbonyl    acetyl    2-quinoylcarbonyl    phenoxyacetyl    benzoyl    methyloxaloyl    pivaloyl    trifluoracetyl    bromoacetyl    hydroxyacetyl    morpholinylacetyl    N,N-dimethylaminoacetyl    N-benzylaminoacetyl    N-phenylaminoacetyl    N-benzyl-N-methylaminoacetyl    N-methyl-N-(2-hydroxyethyl)aminoacetyl    N-methylcarbamoyl    3-methylbutyryl    N-isobutylcarbamoyl    succinoyl (3-carboxypropionyl)    carbamoyl    N-isobutylamino acetyl    N,N-diethylamino acetyl    N-(2-methoxyethyl)aminoacetyl    N-(S-α-methylbenzyl) aminoacetyl    N-(R-α-methylbenzyl) amino acetyl    N-(S-2-tetralin)amino acetyl    N-(R-2-teralin)amino acetyl    N-pyrrolidinylacetyl    N-methyl-N-(2-pyridylethyl)amino acetyl    N-tetrahydroisoquinolylaminoacetyl    N-p-methoxybenzylamino acetyl    ______________________________________

EXAMPLE 24A

The procedure described below illustratespreparation of compounds ofFormula III.Propanamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-(2-phenylethylsulfonyl)-,1S- 1R*(R*),2S*!! andits diastereomer.

Part A:

A solution of methyl methacrylate (7.25 g, 72.5 mmol) and phenethylmercaptan (10.0 g, 72.5 mmol) in 100 mL of methanol was cooled in an icebath and treated withsodium methoxide (100 mg, 1.85 mmol). The solutionwasstirred under nitrogen for 3 h and then concentrated invacuo to givean oil that was taken up in ether and washedwith 1N aqueous potassiumhydrogen sulfate, saturatedaqueous sodium chloride, dried over anhydrousmagnesiumsulfate, filtered and concentrated to give 16.83 g, 97.5%ofmethyl 2-(R,S)-methyl-4-thia-6-phenyl hexanoate as anoil. TLC on SiO₂eluting with 20:1 hexane:ethyl acetate(v:v) R_(f) =0.41.

Part B:

A solution of methyl 2-(R,S)-methyl-4-thia-6-phenylhexanoate (4.00 g,16.8 mmol) in 100 mL ofdichloromethane was stirred at room temperatureandtreated portion wise with meta-chloroperoxybenzoic acid(7.38 g, 39.2mmol) over approximately 40 m. The solutionwas stirred at roomtemperature for 16 h and then filteredand the filtrate washed withsaturated aqueous sodiumbicarbonate, 1N sodium hydroxide, saturatedaqueous sodiumchloride, dried over anhydrous magnesium sulfate,filtered,and concentrated to give 4.50 g, 99% of desiredsulfone. The unpurifiedsulfone was dissolved in 100 mLof tetrahydrofuran and treated with asolution of lithiumhydroxide (1.04 g, 24.5 mmol) in 40 mL of water.Thesolution was stirred at room temperature for 2 m and thenconcentratedin vacuo. The residue was then acidifiedwith 1N aqueous potassiumhydrogen sulfate to pH=1 andthen extracted three times with ethylacetate. Thecombined ethyl acetate solution was washed withsaturatedaqueous sodium chloride, dried over anhydrous magnesiumsulfate,filtered and concentrated to give a white solid.The solid was taken upin boiling ethyl acetate/hexane andallowed to stand undisturbedwhereupon white needlesformed that were isolated by filtration and airdried togive 3.38 g, 79% of2-(R,S)-methyl-3(β-phenethylsulfonyl)propionicacid, mp 91°-93° C.

Part C:

A solution of 2-(R,S)-methyl-3(β-phenethylsulfonyl)-propionicacid (166.1mg, 0.65 mmol),N-hydroxybenzotriazole (HOBT) (146.9 mg, 0.97 mmol),and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC)(145.8 mg, 0.75 mmol) in 4 mL ofanhydrous dimethylformamide (DMF) cooledto 0° C. andstirred under nitrogen for 0.5 h. This solution wasthentreated with 3-(dimethylethyl)amino!carbonyl!(3-methylbutyl)amino-2(R)-hydroxy-1(S)-(phenylmethyl)propylamine(201.9 mg, 0.59 mmol) and stirred at roomtemperature for 16 h. Thesolution was poured into 30 mLof 60% saturated aqueous sodiumbicarbonate solution. Theaqueous solution was then decanted from theorganicresidue. The organic residue was taken up indichloromethane andwashed with 10% aqueous citric acid,brine, dried over anhydrousmagnesium sulfate, filteredand concentrated to give 110.0 mg, 32% of(2R,3S)-3-N-2-(R)-methyl-3-(β-phenethylsulfonyl)propionyl!amido-1-isoamyl-1-(tert-butylcarbamoyl)amino-4-phenyl-2-butanoland(2R,3S)-3-N-2-(S)-methyl-3-(β-phenethylsulfonyl)propionyl!amido-1-isoamyl-1-(tert-butylcarbamoyl)amino-4-phenyl-2-butanol,FAB mass spectrum (MH+)=588. Flashchromatography of the mixture onsilica gel eluting with1:1 hexane:ethyl acetate afforded theseparateddiastereomers.

EXAMPLE 24B

Propanamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-(methylsulfonyl)-1S- 1R*(R*),2S*!!, and itsdiastereomer.

Part A:

A solution of methyl 2-(bromomethyl)-acrylate(26.4 g, 0.148 mol) in 100mL of methanol was treated withsodium methanesulfinate (15.1 g, 0. 148mol) portion wiseover 10 m at room temperature. The solution wasthenstirred at room temperature for a period of 1.25 h and thesolutionconcentrated in vacuo. The residue was thentaken up in water andextracted four times with ethylacetate. The combined ethyl acetatesolution was washedwith saturated sodium chloride, dried overanhydrousmagnesium sulfate, filtered and concentrated to give awhitesolid, 20.7 g which was taken up in boilingacetone/methyl tert-butylether and allowed to standwhereupon crystals of pure methyl2-(methylsulfonylmethyl)acrylate 18.0 g, 68% formed, mp 65°-68.0° C.

Part B:

A solution of methyl 2-(methylsulfonylmethyl)acrylate (970 mg, 5.44mmol) in 15 mL of tetrahydrofuranwas treated with a solution of lithiumhydroxide (270 mg,6.4 mmol) in 7 mL of water. The solution was stirredatroom temperature for 5m and then acidified to pH=1 with1N aqueouspotassium hydrogen sulfate and the solutionextracted three times withethyl acetate. The combinedethyl acetate solution was dried overanhydrous magnesiumsulfate, filtered, and concentrated to give 793 mg,89% of2-(methylsulfonylmethyl) acrylic acid, mp 147°-149.0° C.

Part C:

A solution of 2-(methylsulfonylmethyl) acrylicacid (700 mg, 4.26 nmol)in 20 mL of methanol was chargedinto a Fisher-Porter bottle along width10% palladium oncarbon catalyst under a nitrogen atmosphere. Thereactionvessel was sealed and flushed five times with nitrogen andthenfive times with hydrogen. The pressure wasmaintained at 50 psig for 16 hand then the hydrogen wasreplaced with nitrogen and the solutionfiltered through apad of celite to remove the catalyst and thefiltrateconcentrated in vacuo to give 682 mg 96% of2-(R,S)-methyl-3-methylsulfonyl propionic acid.

Part D:

A solution of 2-(R,S)-methyl-3(methylsulfonyl)propionicacid (263.5 mg,1.585 mmol), N-hydroxybenzotriazole(HOBT) (322.2 mg, 2.13 mmol),and1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC)(339.1 mg, 1.74 mmol) in 4 mL ofanhydrous dimethylformamide (DMF) cooledto 0° C. andstirred under nitrogen for 0.5 h. This solution wasthentreated with 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino-2(R)-hydroxy-I(S)-(phenylmethyl)propylamine(543.5 mg, 1.58 mmol) and stirred at roomtemperature for 16 h. Thesolution was poured into 60 mLof 60% saturated aqueous sodiumbicarbonate solution. Theaqueous solution was then decanted from theorganicresidue. The organic residue was taken up indichloromethane andwashed with 10% aqueous citric acid,brine, dried over anhydrousmagnesium sulfate, filteredand concentrated to give 471.8 mg, 60% ofPropanamide,N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-(methylsulfonyl)-,1S- 1R*(R*),2S*!!- and itsdiastereomer.

EXAMPLE 25 Preparation of Sulfone Inhibitors FromL-(+)-S-acetyl-β-mercaptoisobutyricAcid

Part A:

Promanamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-S-acetyl)-1S- 1R*),2S*!!-.

A round-bottomed flask was charged with(2R,3R)-3-amino-1-isoamyl-1-(tert-butylcarbamoyl)amino-4-phenyl-2-butanol(901.5mg, 2.575 mmol), L-(+)-S-acetyl-b-mercaptoisobutyricacid (164.5 mg,2.575 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride(EDC) (339.1 mg, 1.74 mmol), and 10 mL of CH₂ Cl₂andallowed to stir at room temperature for 16 h. Thesolution wasconcentrated in vacuo and the residue takenup in ethyl acetate, washedwith 1N KHSO₄ sat. aq. NaHCO₃,brine, dried over anhydrous MgSO₄,filtered andconcentrated to give an oil that was purified byradialchromatography on SiO₂ eluting with ethyl acetate to givethe pureproduct, 800 mg, 63%.

Part B:

Propanamide, N- 3-1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-mercapto)-,1S- 1R*(R*),2S*!!-.

A solution of 1S- 1R*(R*),2S*!!-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-S-acetyl)propanamide(420mg, 0.85 mmol) in 10 mL of methanol wastreated with anhydrous ammoniafor ca. 1 m at 0° C. Thesolution was stirred at that temperature for 16h and thenconcentrated in vacuo to give 380 mg, 99%, of thedesiredproduct that was used directly in the next step withoutfurtherpurification.

Part C:

Propanamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-S-methyl-,1S- 1R*(R*),2S*!!-.

A solution of 1S- 1R*(R*),2S*!!-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-mercapto)propanamide(380mg, 0.841 mmol) in 10 mL of dry tolueneunder nitrogen was treated inrapid succession with 1,8-diazabicyclo 5.4.0!undec-7-ene, (DBU), (128.1mg. 0.841 mmol) and iodomethane (119.0 mg, 0.841 mmol). After 0.5 hatroom temperature the reaction was found to be completeand the solutionwas diluted with ethyl acetate washedwith 1N KHSO₄, sat. aq. NaHCO₃,brine. After the solutionwas dried over anhydrous MgSO₄, filtered andconcentratedin vacuo the desired product was obtained as white foamwasobtained, 370 mg, 94.5%, that was used directed in thenext step.

Part D:

Propanamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-(methylsulfonyl)-,1S- 1R*(R*),2S*!!-.

A solution of 1S- 1R*(R*),2S*!!-N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl-3-S-methyl)propanamide(340mg, 0.73 mmol) and sodium perborate (500 mg, 3.25 mmol) in 30 mL ofglacial acetic acid was warmedto 55° C. for 16 h. The solution wasconcentrated in vacuoand then the residue taken up in ethyl acetate,washedwith water, sat. aq. NaHCO₃, brine, dried over anhydrousMgSO₄,filtered and concentrated to give the desiredproduct as a white solid,350 mg, 96%.

EXAMPLE 26

The compounds shown in Tables 13A and 13B wereprepared generallyaccording to the procedure set forth inExamples 24 and

                  TABLE 13A    ______________________________________     ##STR154##    R'    ______________________________________    CH.sub.3    CH.sub.3 CH.sub.2    CH.sub.3 CH.sub.2 CH.sub.2    PhCH.sub.2 CH.sub.2    PhCH.sub.2    Ph    (CH.sub.3).sub.2 CH    HOCH.sub.2 CH.sub.2     ##STR155##     ##STR156##     ##STR157##    CH.sub.2CHCH.sub.2    ______________________________________

                  TABLE 13B    ______________________________________     ##STR158##           R'   R.sub.1    ______________________________________           CH.sub.3                CH(CH.sub.3).sub.2           CH.sub.3                CH(CH.sub.3).sub.3    ______________________________________

EXAMPLE 27 Preparation of 2(S)-methyl-3-methylsulfonyl)propionicAcid

To a solution of 10 g of D-(-)-S-benzoyl-b-mercaptioisobutyricacidt-butyl ester in 20 mL of methanolwas bubbled in gaseous ammonia at 0°C. The reaction wasallowed to then warm to room temperature, stirredovernightand concentrated under reduced pressure. The resultingmixtureof a solid (benzamide) and liquid was filtered toprovide 5.21 g of apale oil which then solidified. Thiswas identified as2(S)-methyl-3-mercaptopropionic aidt-butyl ester.

To a solution of 5.21 g of 2(S)-methyl-3-mercaptopropionicacid t-butylester in 75 mL of toluene at0° C. was added 4.50 g of 1,8-diazabicyclo5.40!undec-7-eneand 1.94 mL of methyl iodide. After stirring atroomtemperature for 2.5 hours, the volatiles were removed,ethyl acetateadded, washed with dilute hydrochloric acid,water, brine, dried andconcentrated to afford 2.82 g of apale oil, identified as2(S)-methyl-3-(thiomethyl)propionicacid t-butyl ester.

To a solution of 2.82 g of 2(S)-methyl-3-(thiomethyl)propionicacidt-butyl ester in 50 mL of aceticacid was added 5.58 g of sodiumperborate and the mixtureheated to 55° C. for 17 hours. The reaction waspoured intowater, extracted with methylene chloride, washed withaqueoussodium bicarbonate, dried and concentrated toafford 2.68 g of2(S)-methyl-3-(methylsulfonyl)propionicacid t-butyl ester as a whitesolid.

To 2.68 g of 2(S)-methyl-3-(methylsulfonyl)propionicacid t-butyl esterwas added 20 mL of 4Nhydrochloric acid/dioxane and the mixture stirredat roomtemperature for 19 hours. The solvent was removed underreducedpressure to afford 2.18 g of crude product, whichwas recrystallized fromethyl acetate/hexane to yield 1.44 gof2(S)-methyl-3-(methylsulfonyl)propionic acid as whitecrystals.

EXAMPLE 28

This example illustrates preparation ofcompounds wherein t is 1.

4-N-benzyl itaconamide. ##STR159##

A 500 mL three necked round bottomed flaskequipped with a droppingfunnel, mechanical stirrer,nitrogen inlet and reflux condenser wascharged withitaconic anhydride (33.6 g, 0.3 mol) and 150 mL oftoluene.This solution was added a solution of benzylamine (32.1 g,0.3mol) in 50 mL of toluene dropwise over 30 m at roomtemperature. Thesolution was stirred at this temperaturean additional 3 h and then thesolid product isolated byfiltration on a Buchner funnel. The crudeproduct, 64.6 g98%, was recrystallized from 300 mL of isopropyl alcoholtogive after two CROPS 52.1 g, 79% of pure product, mp 149°-150° C.

2(R)-Methyl 4-N-benzyl succinamide. ##STR160##

A large Fisher-Porter bottle was charged withthe acid from the abovereaction (10.95 g, 0.05 mol),rhodium (R,R)-DiPAMP (220 mg, 0.291 mmol)and 125 mL ofdegassed methanol. The solution was then hydrogenated at40psig for 16 h at room temperature. After the hydrogenuptake ceased, thevessel was opened and the solutionconcentrated in vacuo to give a yellowsolid, 11.05 g, 100%.The product was then taken up in absolute ethanolandallowed to stand whereupon crystals of the desired productformed,7.98 g, 72%, mp 127°-129 ° C. α!_(D) @ 25° C.=+14.9° (c=1.332, EtOH), ¹H nmr (CDCl₃) 300 MHz 7.30(m, 5H),6.80(brs, 1H), 4.41(d, J=5.8 Hz, 2H),2.94(m, 1H), 2.62(dd,J=8.1, 14.9 Hz, 1H), 2.33(dd, J=5.5, 14.9 Hz, 1H),1.23(d,J=7.2 Hz, 3H).

4-N(4-methoxybenzyl)itaconamide . ##STR161##

A 500 mL three necked round bottomed flaskequipped with a droppingfunnel, mechanical stirrer,nitrogen inlet and reflux condenser wascharged withitaconic anhydride (44.8 g, 0.4 mol) and 150 mL oftoluene.This solution was added a solution of 4-methoxybenzylamine(54.8g, 0.4 mol) in 50 mL of toluene dropwise over 30 m atroom temperature.The solution was stirred at thistemperature an additional 2 h and thenthe solid productisolated by filtration on a Buchner funnel. Thecrudeproduct was recrystallized from ethyl acetate/ethanol togive aftertwo crops 64.8 g, 65% of pure product, mp 132°-134° C., ¹ H nmr (CDCl₃)300 MHz 7.09(d, J=9.1 Hz, 2H), 6.90(brt,J=5.9 Hz, 1H), 6.74(d, J=9.1 Hz,2H), 6.22(s, 1H), 5.69(s,1H), 4.24(d, J=5.9 Hz, 2H), 3.69(s, 3H),3.15(s, 2H). ¹³ Cnmr (CDCl₃) 170.52, 169.29, 159.24, 135.61, 131.08,129.37,128.97, 114.36, 55.72, 43.37, 40.58.

2(R)-Methyl 4-N(4-methoxybenzyl)succinamide. ##STR162##

A large Fisher-Porter bottle was charged withthe acid from the abovereaction (5.00 g, 0.02 mol),rhodium (R,R)-DiPAMP (110 mg, 0.146 mmol)and 50 mL ofdegassed methanol. The starting acid was notcompletelysoluble initially, but as the reaction progressed thesolutionbecame homogeneous. The solution was thenhydrogenated an 40 psig for 16h at room temperature. Afterthe hydrogen uptake ceased, the vessel wasopened and thesolution concentrated in vacuo to give a yellow solid.Thecrude product was then taken up in ethyl acetate and washedthreetimes with sat. aq. NaHCO₃ solution. The combinedaqueous extracts wereacidified to pH=1 with 3N HCl andthen extracted three times with ethylacetate. Thecombined ethyl acetate extracts were washed with brine,driedover anhyd. MgSO₄, filtered and concentrated to givethe expected productas a white solid, 4.81 g, 95%. Thismaterial was recrystallized from amixture of methyl ethylketone/hexane to give 3.80 g, 75% of pureproduct, α!_(D) @ 25° C.=+11.6° (c=1.572, MeOH). ¹ H nmr (CDCl₃) 300 MHz11.9(brs,1H), 7.18(d, J=9.2 Hz, 2H), 6.82(d, J=9.2 Hz, 2H),6.68(brt,J=5.6 Hz, 1H), 4.33(d, J=5.6 Hz, 2H), 3.77(s, 3H),2.92(ddq,J=7.9, 5.4, 7.3 Hz, 1H), 2.60(dd, J=5.4, 15.0 Hz, 1H),2.30(dd,J=7.9, 15.0 Hz, 1H),1.22(d, J=7.3 Hz, 3H).

Butanediamide, N'- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-N-4-methoxyphenylmethyl-2methyl,1S- 1R*(2R*),2S*!!- ##STR163##

A 50 mL round bottomed flask was charged with2(R)-methyl4-N(4-methoxybenzyl)succinamide (588 mg, 2.35 mmol),N-hydroxybenzotriazole (511 mg, 3.34 mmol) and 6 mLof DMF. The solutionwas cooled to 0° C. and treatedwith1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(502 mg,2.62 mmol) for 20 m. A solution of (2R,3S)-3-amino-1-(3-methylbutyl)-1-(1,1-dimethylethyl)amino!carbonyl)-4-phenyl-2-butanol(782 mg,2.24 mmol)in 2 mL of DMF was added and the solutionstirred at room temperature fora period of 24 h. Thesolution was concentrated in vacuo and poured into50 mL of50% sat. aq. NaHCO₃, the aqueous phase was extracted withCH₂Cl₂. The organic phase was washed with 5% citric acid,NaHCO₃, brine,dried over anhyd. MgSO₄, filtered andconcentrated to give an oil thatwas purified by radialchromatography on SiO₂ eluting with hexane/ethylacetate togive 790 mg, 59% of pure product as a white foam.

Butanediamide, N'- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-N-phenylmethyl-2-methyl,1S- 1R*(2R*),2S*!!- ##STR164##

A 50 mL round bottomed flask was charged with2(R)-methyl4-N-(benzyl)succinamide (243 mg, 1.1 mmol),N-hydroxybenzotriazole (213mg, 1.39 mmol) and 3 mL of DMF.The solution was cooled to 0° C. andtreated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(228 mg, 1.17 mmol) for 20 m. A solution of(2R,3S)-3-amino-1-(3-methylbutyl)-1-(1,1-dimethylethyl)amino!carbonyl)-4-phenyl-2-butanol (327 mg, 0.95mmol) in 2 mL of DMF wasadded and the solution stirred at roomtemperature for aperiod of 24 h. The solution was concentrated in vacuoandpoured into 50 mL of 50% sat. aq. NaHCO₃, the aqueous phasewasextracted with CH₂ Cl₂. The organic phase was washedwith 5% citric acid,NaHCO₃, brine, dried over anhyd.MgSO₄, filtered and concentrated to givean oil that waspurified by flash chromatography on SiO₂ elutingwithhexane/ethyl acetate to give 370 mg, 70% of pure product asa whitefoam.

EXAMPLE 29

Following the procedure generally as see forthin Example 28, as well asin Examples 31-45, the compoundsshown in Table 14 were

                                      TABLE 14    __________________________________________________________________________     ##STR165##    R.sup.1 R.sup.30               R.sup.31                   R.sup.32                       X' R.sup.33                                  R.sup.34    __________________________________________________________________________    H       H  H   H   N  H       H    H       H  H   H   O  H       --    H       H  H   H   O  CH.sub.3                                  --    CH.sub.3            H  H   H   N  H       H    CH.sub.3            H  H   H   O  H       --    H       H  CH.sub.3                   H   N  H       H    H       H  CH.sub.3                   H   O  H       --    CH.sub.3            CH.sub.3               H   H   N  H       H    CH.sub.3            CH.sub.3               H   H   O  H       --    CH.sub.3            CH.sub.3               H   H   O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    H       H  CH.sub.3                   CH.sub.3                       N  H       H    H       H  CH.sub.3                   CH.sub.3                       O  H       --    H       H  CH.sub.3                   CH.sub.3                       O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    CH.sub.3            H  CH.sub.3                   H   N  H       H    CH.sub.3            H  CH.sub.3                   H   N  H       CH.sub.3    CH.sub.3            H  CH.sub.3                   H   N  CH.sub.3                                  CH.sub.3    CH.sub.3            H  CH.sub.3                   H   O  H       --    CH.sub.3            H  CH.sub.3                   H   N  H       CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3    OH      H  H   H   N  H       H    OH      H  H   H   O  H       --    H       H  OH  H   N  H       H    H       H  OH  H   O  H       --    CH.sub.2            H  H   H   N  H       H    CH.sub.2 C(O)NH.sub.2            H  H   H   N  H       H    CH.sub.2 C(O)NH.sub.2            H  H   H   O  H       --    CH.sub.2 C(O)NH.sub.2            H  H   H   O  CH.sub.3                                  --    CH.sub.2 Ph            H  H   H   N  H       H    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  H       H    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  H       --    CH.sub.3            H  CH.sub.3                   CH.sub.3                       O  H       CH.sub.3    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  CH.sub.3                                  CH.sub.3    __________________________________________________________________________

EXAMPLE 30

Following the procedure generally as set forthin Example 28, as well asExamples 31-45, the compoundsshown in Table 15 were

                  TABLE 15    ______________________________________     ##STR166##     ##STR167##     ##STR168##     ##STR169##    ______________________________________

EXAMPLE 31 Preparation of 3(S)-N-(2-quinolinylcarbonyl)-L-asparaginyl!amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl)

Part A:

Preparation ofN-3(S)-(Benzyloxycarbonyl)amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl).A solution of 20 g (67 mmol) ofN-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane in 140 mL ofisopropylalcohol was treated with 83 g (952 mmol) of isoamylamineandrefluxed for one hour. The solution was cooled,concentrated, hexaneadded and the resulting solid filteredto afford 22.4 g of the desiredproduct.

Part B:

Preparation ofN-3(S)-(Benzyloxycarbonyl)amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl)-N-(t-butyloxycarbonyl).To a solution of 22.4 g (58.3mmol)of product from Part A above, 6.48 g (64.1 mmol) oftriethylamineand 150 mg of N,N-dimethyl-4-aminopyridine in200 mL of tetrahydrofuranat 0° C. was added 12.7 g (58.3 mmol) of di-t-butylpyrocarbonate in 10mL of THF. After3.5 hours at room temperature, the volatiles wereremoved,ethyl acetate added and washed with 5% citric acid, sat'dNaHCO₃,dried and concentrated to afford 30 g of crudeproduct. Chromatography onsilica gel using 20% ethylacetate/hexane afforded 22.5 g (79%) of thedesired product.

Part C:

Preparation of N-3(S)-N-benzyloxycarbonyl-L-asparaginyl!amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl)-N-(t-butyloxycarbonyl).A solution of 22.5 gof productfrom Part B above in 200 mL of ethanol washydrogenated over 5.9 g of 10%palladium-on-carbon under50 psig hydrogen for one hour. The catalyst wasfilteredand the solvent removed under reduced pressure to afford15.7 gof free amine. This was dissolved in 130 mL of DMFand 4.54 g (44.9 mmol)of N-methylmorpholine an added to amixture of 13.3 g (49.9 mmol)N-benzyloxy-carbonyl-L-asparagine,11.5 g (74.9 mmol) ofN-hydroxybenzotriazole and10.5 g (54.9 mmol) of EDC in 120 mL of DMF at0° C., which hadbeen preactivated for one hour prior to the addition.Themixture was stirred for 2 hours at 0° C. and then for 12 hours atroom temperature. The reaction was poured into 1 Lof sat'd aqueoussodium bicarbonate, the solid collected,dissolved in ethyl acetate,washed with water, sat'd sodiumbicarbonate, 5% citric acid and brine,dried andconcentrated to afford 16.7 g of the desired product.

Part D:

Preparation of N-3(S)-N-(2-quinolinylcarbonyl)-L-asparaginyl!amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl)-N-(t-butyloxycarbonyl).A solution of 16.7 g(28.0 mmol)of product from Part C in 250 mL of methanolwas hydrogenated over 6.0 gof 10% palladium-on-carbon andunder 50 psig hydrogen for one hour. Thecatalyst wasfiltered and the solution concentrated to afford 10.0 goffree amine. This was dissolved in 100 mL of methylenechloride, 4.35 g(43 mmol) of N-methylmorpholine was addedfollowed by 5.53 g (20.5 mmol)of quinoline-2-carboxylicacid, N-hydroxysuccinimide ester. This wasstirred at roomtemperature overnight, the solvent removed, ethylacetateadded and washed with 5% citric acid, sat'd sodiumbicarbonate,brine, dried and concentrated to afford 14 g ofcrude product.Recrystallization from ethyl acetate andhexane afforded 10.5 g (83%) ofdesired product.

Part E:

Preparation of N-3(S)-N-(2-quinolinylcarbonyl)-L-asparaginyl!amino-2(R)-hydroxy-4-phenylbutylamine,N-(3-methylbutyl).To 80 mL of 4Nhydrochloric acid in dioxane was added 9.17 g (14.8 mmol)ofproduct from Part D above. After one hour, the productbecomes gummy.The solvents were removed, diethyl etheradded and removed and theresidue dissolved in 20 mL ofmethanol. This solution was added to 400 mLof sat'daqueous sodium bicarbonate, the solids collected, washedwithacetone and hexane and dried in vacuo over P₂ O₅ toafford 4.75 g of thedesired product.

EXAMPLE 32A Preparation of Benzyl 2,2,3(R)-trimethylsuccinate

Part A:

Preparation of Methyl (S)-lactate, 2-methoxy-2-propylether. To a mixtureof methyl (S)-(-)-lactate(13.2 g, 100 mmol) and, 2-methoxypropene (21.6g,300 mmol) in CH₂ Cl₂ (150 ml) was added POCl₃ (7 drops) atr.t. and theresulting mixture was stirred at thistemperature for 16 hours. After theaddition of Et₃ (10 drops), the solvents were removed in vacuo to give20.0 g of(98%) desired product.

Part B:

Preparation of 2(S)-hydroxypropanal, 2-methoxy-2-propyl ether. To asolution of compound from Part A(20.0 g) in CH₂ Cl₂ (100 ml) was addedDIBAL (65 ml of 1.5Msolution in toluene, 97.5 mmol) dropwise at -78° C.for 45 min., then stirring was continued at the temperature foranother45 min. To this cold solution was added MeOH(20 ml), saturated NaClsolution (10 ml) and allowed thereaction mixture to warm up to r.t. anddiluted with ether(200 ml), MgSO₄ (150 g) was added and stirred foranother 2 h. The mixture was filtered and the solid was washed twicewithether. The combined filtrates were rotavaped toafford 11.2 g (78%) ofthe desired aldehyde.

Part C:

Preparation of 2(S)-hydroxy-cis-3-butene, 2-methoxy-2-propyl ether. To asuspension ofethyltriphenylphosphonium bromide (28 g, 75.5 mmol) inTHF(125 ml) was added KN (TMS)₂ (15.7 g, 95%, 75 mmol) inportions at 0°C. and stirred for 1 h at the temperature.This red reaction mixture wascooled to -78° C. and to thiswas added a solution of aldehyde from PartB (11 g, 75 mmol)in THF (25 ml). After the addition was completed,theresulting reaction mixture was allowed to warm up to r.t.and stirredfor 16 h. To this mixture was added saturatedNH₄ Cl (7.5 ml) andfiltered through a pad of celite with athin layer of silica gel on thetop. The solid was washedtwice with ether. The combined filtrates wereconcentratedin vacuo to afford 11.5 g of crude product. Thepurificationof crude product by flash chromatography(silica gel, 10:1 Hexanes/EtoAc)affording 8.2 g (69%) purealkene.

Part D:

Preparation of 2(S)-hydroxy-cis-3-butene. Amixture of alkene from Part C(8.2 g) and 30% aqueous aceticacid (25 ml) was stirred at r.t. for 1hour. To thismixture was added NaHCO₃ slowly to the pH˜7, thenextractedwith ether (10 ml×5). The combined ethersolutions were dried (Na₂ SO₄)and filtered. The filtratewas distilled to remove the ether to give 2.85g (64%) purealcohol, m/e=87(M+H).

Part E:

Preparation of 2,2,3-trimethyl-hex-(trans)-4-enoicacid. To a mixture ofalcohol from Part D (2.5 g, 29 mmol) and pyridine (2.5 ml) in CH₂ Cl₂(60 ml) was addedisobutyryl chloride (3.1 g, 29 mmol) slowly at 0° C.Theresulting mixture was stirred at r.t. for 2 hours thenwashed with H₂O (30 ml×2) and sat. NaCl (25 ml). Thecombined organic phases were dried(Na₂ SO₄), concentratedto afford 4.2 g (93%) ester2(S)-hydroxy-cis-3-butenylisobutyrate. This ester was dissolved in THF(10 ml) andwas added to a 1.0M LDA soln. (13.5 ml of 2.0M LDA solutioninTHF and 13.5 ml of THF) slowly at -78° C. The resultingmixture wasallowed to warm up to r.t. and stirred for 2 hand diluted with 5% NaOH(40 ml). The organic phase wasseparated, the aqueous phase was washedwith Et₂ O (10 ml).The aqueous solution was collected and acidified with6NHCl to pH˜3. The mixture was extracted with ether (30 ml×3). Thecombined ether layers were washed with sat. NaCl(25 ml), dried (Na₂ SO₄)and concentrated to afford 2.5 g(60%) of desired acid, m/e=157 (M+H).

Part F:

Preparation of benzyl 2,2,3(S)-trimethyl-trans-4-hexenoate. A mixture ofacid from Part E (2.5 g, 16 mmol),BnBr (2.7 g, 15.8 mmol), K₂ CO₃ (2.2g, 16 mmol), NaI (2.4 g)in acetone (20 ml) was heated at 75° C. (oilbath) for 16 h.The acetone was stripped off and the residue wasdissolvedin H₂ O (25 ml) and ether (35 ml). The ether layerwasseparated, dried (Na₂ SO₄) and concentrated to afford 3.7 g(95%) ofbenzyl ester, m/e=247 (M+H).

Part G:

Preparation of benzyl 2,2,3(R)-trimethylsuccinate.To a well-stirredmixture of KMnO₄ (5.4 g, 34, 2 mmol), H₂ O (34 ml), CH₂ Cl₂ (6 ml)andbenzyltriethylammonium chloride (200 mg) was added asolution of esterfrom Part F (2.1 g, 8.54 mmol) and aceticacid (6 ml) in CH₂ Cl₂ (28 ml)slowly at 0° C. The resultingmixture was stirred at the temperature for2 h then r.t.for 16 h. The mixture was cooled in an ice-water bath,tothis was added 6N HCl (3 ml) and solid NaHSO₃ in portionsuntil the redcolor disappeared. The clear solution wasextracted with CH₂ Cl₂ (30ml×3). The combined extractswere washed with sat. NaCl solution, dried(Na₂ SO₄) andconcentrated to give an oil. This oil was dissolved inEt₂ O(50 ml) and to this was added sat. NaHCO₃ (50 ml).The aqueous layer wasseparated and acidified with 6N HClto pH˜3 then extracted with Et₂ O (30ml×3). Thecombined extracts were washed with sat. NaCl solution (15 ml),dried (Na₂ SO₄) and concentrated to afford 725 mg (34%)of desired acid,benzyl 2,2,3(R)-trimethylsuccinate,m/e=251(M+H).

EXAMPLE 32B

Part A:

Preparation of Butanediamide, N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2,3,3-trimethyl-1S-, 1R*(2S*),2S*!!-

To a well-stirred solution of benzyl 2,2,3(R)-trimethylsuccinate(225 mg,0.9 mmol) in DMF (1.0 ml) wasadded HOBt (230 mg, 1.5 mmol). The clearreaction mixturewas then cooled to 0° C., to this was added EDC (210 mg,1.1 mmol) and stirred for 1 h at the temperature. To this coldmixturewas added a powder of the butanol of Example 28 used to prepare thebutaneamide therein, (350 mg, 1.0 mmol)and DMF (0.5 ml). The resultingreaction mixture wasstirred for 2 h at 0° C. and 16 h at r.t. After theremovalof DMF (≦40° C.), a solution of 60% sat. NaHCO₃ (10 ml) wasadded.This mixture was extracted with EtOAc (10 ml×2).The extracts werecombined and washed with sat. NaHCO₃ (10 ml×2), 5% citric acid (10ml×2), H₂ O (10 ml), sat. NaCl(10 ml) and dried (Na₂ SO₄) thenconcentrated to afford 512 mg (98%) of 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-2,2,3-trimethyl-4-oxo,1S- 1R*(3S*),2S*!!-benzyl ester asa white solid, m/e=582 (M+H).

Part B:

A mixture of benzyl ester from Part A (480 mg,0.825 mmol), 10% Pd/C (450mg) in MeOH (25 ml) washydrogenated (H₂, 50 psi) for 1/2 h at r.t. Themixturewas filtered and the solid was washed with MeOH (10 ml).Thecollected filtrates were concentrated to afford a crudeacid as a whitesolid. The crude acid was dissolved inEt₂ O-EtOAc (10:1, 25 ml) and thesolution was washed withsat. NaHCO₃ (25 ml) then 5% NaOH (10 ml). Thecombinedaqueous layers were cooled to 0° C. and acidifiedwithconcentrated HCl no pH˜1 then extracted with Et₂ O-EtOAC(10:1, 25ml×3). The combined extracts were washed withsat. NaCl (15 ml ), dried(Na₂ SO₄) and concentrated toafford 307 mg (75.7%) of pure Butanoicacid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-2,2,3-trimethyl-4-oxo-,1S- l R*(3S*),2S*!!-, as a white solid, m/e=491 (M+H).

Part C:

Butanoic acid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-2,2,3-trimethyl-4-oxo-,1S- 1R*(3S*),2S*!!-, as a white solid, m/e=491 (M+H).

To a well-stirred solution of the acid from PartB (245 mg, 0.5 mmol) inDMF (0.5 ml) was added HOBt (153 mg, 1.0 mmol) and EDC (143 mg, 0.75mmol) at 0° C. Afterstirring at 0° C. for 2 h, NH₄ OH (0.63 ml of 28%NH₄ OH, 5 mmol) was added and stirred at 0° C. for 2 h, r.t. for 16h.The removal of DMF (≦40° C.) gave a white solid. Thepurification ofthe crude product by flash chromatography(silica gel, 5% MeOH/CH₂ Cl₂ )gave 172 mg (70%) of pureamide as a white solid, m/e=491 (M+H).

EXAMPLE 33

Preparation of methyl 2,2-dimethyl-3-methyl succinate, (R)and (S)isomers.

Part A:

Preparation of methyl 2,2-dimethyl -3-oxo-butanoate.A 250 ml RB flaskequipped with magnetic stirbar and N₂ inlet was charged with 100 ml dryTHF and 4.57 g(180 mmol) of 95% NaH. The slurry was cooled to -20° C.and10 g (87 mmol) methyl acetoacetate was added dropwisefollowed by 11.3ml (181 mmol) CH₃ I. The reaction wasstirred at 0° C. for 2 hours andlet cool to room temperatureovernight. The reaction was filtered toremove NaI anddiluted with 125 ml Et₂ O. The organic phase waswashedwith 1×100 mL 5% brine, dried and concentrated in vacuo toa darkgolden oil that was filtered through a 30 g plug ofsilica gel withhexane. Concentration in vacuo yielded10.05 g of desired methyl ester,as a pale yellow oil,suitable for use without further purification.

Part B:

Preparation of methyl2,2-dimethyl-3-0-(trifluoromethanesulfonate)-but-3-enoate. A 250 mlRBflask equipped with magnetic stir bar and N₂ inlet wascharged with 80mL dry THF and 5.25 ml (37.5 mmol)diisopropylamine was added. Thesolution was cooled to-25° C. (dry ice/ethylene glycol) and 15 ml (37.5mmol) of2.5M n-BuLi in hexanes was added. After 10 minutes asolution of5 g (35 mmol) 1 in 8 ml dry THF was added. Thedeep yellow solution wasstirred at -20° C. for 10 min. then12.4 g N-phenylbis(trifluoromethanesulfonimide) (35 mmol)was added. The reaction wasstirred @ -10° C. for 2 hours,concentrated in vacuo and partionedbetween ethyl acetateand sat. NaHCO₃. The combined organic phase waswashedwith NaHCO₃, brine and conc. to an amber oil that wasfilteredthrough 60 g silica gel plug with 300 mL 5% ethylacetate/hexane Conc. invacuo yielded 9.0 g light yellow oilthat was diluted with 65 ml ethylacetate and washed with2×50 ml 5% aq K₂ CO₃, 1×10 mL brine, dried overNa₂ SO₄ andconc. in vacuo to yield 7.5 g (87%) vinyl triflate,(m/e=277(M+H) suitable for use without furtherpurification.

Part C:

Preparation of methyl 2,2-dimethyl-3-carboxyl-but-3-enoate. A 250 mlFisher Porter bottle was chargedwith 7.5 g (27 mmol) of compoundprepared in B, 50 ml dryDMF, 360 mg (1.37 mmol) triphenyl phosphine and155 mg (.69 mmol) Pd(II)(OAc)₂. The reaction mixture was purgedtwicewith N₂ then charged with 30 psi CO. Meanwhile a solutionof 20 mldry DMF and 7.56 ml (54 mmol) NEt₃ was cooled to0° C. to this was added2.0 g (43 mmol) of 99% formic acid.The mixture was swirled and added tothe vented FisherPorter tube. The reaction vessel was recharged to 40psiof CO and stirred 6 hours @ room temperature. The reactionmixture wasconcentrated in vacuo and partioned between100 mL of ethyl acetate and75 mL 5% aq K₂ CO₃. The aqueousphase was washed with 1×40 mL additionalethyl acetate andthen acidified with conc. HCl/ice. The aqueous phasewasextracted with 2×70 mL of ethyl acetate and the organicswere driedand conc. to yield 3.5 g (75%) white crystals, mp72°-75° C., identifiedas the desired product (m/e=173 (M+H).

Part D:

Preparation of methyl 2,2-dimethyl-3-methylsuccinate,isomer #1. A steelhydrogenation vesselwas charged with 510 mg (3.0 mmol) acrylic acid,from PartC, and 6 mg Ru (acac)₂ (R-BINAP) in 10 ml degassed MeOH.Thereaction was hydrogenated at 50 psi/room temperaturefor 12 hours. Thereaction was then filtered throughcelite and conc. to 500 mg clear oilwhich was shown to bea 93:7 mixture of isomer #1 and #2, respectivelyasdetermined by GC analysis using a 50M β-cyclodextrincolumn: 150° C.-15min. then ramp 2° C./min.; isomer #1,17.85 min., isomer #2, 18-20 min.

Part E:

Preparation of methyl 2,2-dimethyl-3-methylsuccinate,Isomer #2. A steelhydrogenation vessel-was charged with 500 mg (2.9 mmol) acrylic acid,Part C,and 6 mg Ru(OAc) (acac) (S-BINAP) in 10 ml degassed MeOH.Thereaction was hydrogenated at 50 psi/room temperaturefor 10 hours. Thereaction was filtered through celite andconcentrated in vacuo to yield490 mg of product as a 1:99 mixture of isomers #1 and #2, respectively,as determinedby chiral GC as above.

EXAMPLE 34 Preparation of 3-(1,1-dimethylethyl)amino!carbonyl!-(3-methylbutyl)amino!-2(R)-hydroxy-1(S)-(phenylmethyl)propylamine,1.

Part A:

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in amixture of807 mL of methanol and 807 mL of tetrahydrofuranat -2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solidsodium borohydride over onehundred minutes. The solventswere removed under reduced pressure at 40°C. and the residuedissolved in ethyl acetate (approx. 1 L). The solutionwaswashed sequentially with 1M potassium hydrogen sulfate,saturatedsodium bicarbonate and then saturated sodiumchloride solution. Afterdrying over anhydrous magnesiumsulfate and filtering, the solution wasremoved underreduced pressure. To the resulting oil was addedhexane(approx. 1 L) and the mixture warmed to 60° C. with swirling.Aftercooling to room temperature, the solids werecollected and washed with 2L of hexane. The resultingsolid was recrystallized from hot ethylacetate and hexaneto afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150°-151° C. andM+Li⁺ =340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) ofpotassium hydroxide in968 mL of absolute ethanol at roomtemperature, was added 32.3 g (0.097mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. After stirringfor fifteenminutes the solvent was removed under reduced pressure andthesolids dissolved in methylene chloride. After washing withwater,drying over magnesium sulfate, filtering and stripping,one obtains 27.9g of a white solid. Recrystallization fromhot ethyl acetate and hexaneafforded 22.3 g (77% yield)ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane,mp102°-103° C. and MH⁺ 298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (30.1 g, 0.10 mol) and 165 mLofisoamylamine in 150 mL of isopropyl alcohol was heated toreflux for2.5 hours. The solution was cooled to roomtemperature, concentrated invacuo and then recrystallized.The product was isolated by filtration andfrom ethylacetate/hexane to afford 31.7 g (81%) of N3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl!N-isoamylamine.

Part D:

A solution of N 3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl!, N-isoamylamine in 10 ml oftetrahydrofuran was treated withtert-butylisocyanate (267 mg, 2.70 mmol) at room temperature for 5minutes. Thesolvent was removed in vacuo and replaced with ethylacetate.The ethyl acetate solution was washed with 5%citric acid, water, andbrine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo togive 1.19 g, 97% ofN-benzyloxycarbonyl-3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2(R)-hydroxy-1(S)-(phenylmethyl)propylamine,MH⁺m/z=470.

Part E:

A solution of (37.3 g, 77 mmol) of product fromPart D in 100 mL ofmethanol was hydrogenated over 10%palladium-on-carbon for 4 hours toafford 26.1 g of thedesired product.

EXAMPLE 35 Preparation of Butanediamide, N- 3-1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*,2S*!!-

Part A:

To a solution of 102 mg (0.29 mmol) of Example 34 Part E and 70 mg (0.89mmol) of pyridine in 2 mL ofmethylene chloride was added 29 mg (0.29mmol) of succinicanhydride. After 2 hours, ethyl acetate was added andthenextracted with saturated NaHCO. The aqueous layer wasacidified,reextracted with ethyl acetate, washed withsaturated brine, dried overmagnesium sulfate, filtered andconcentrated in vacuo to afford 78 mg(60%) of butanoicacid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino-4-oxo-,1S- 1R*,2S*!-.

Part B:

The compound of Part A was activated withEDC and N-hydroxybenzotriazolein N,N-dimethylformamide andthen reacted with ammonia to generate thedesired finalcompound.

EXAMPLE 36

Part A:

To a solution of 4.60 g (24.7 mmol) oftrans-diethyl1,2-cyclopropanedicarboxylate in 100 mL of 50:50 v:vtetrahydrofuran/waterwas added 1.24 g (29.6 mmol) of lithiumhydroxide.After 17 hours, the tetrahydrofuran was removed invacuo, the water layerwashed with ethyl acetate, acidifiedwith 1N hydrochloric acid andreextracted with ethyl acetate.The organic layer was dried and strippedto afford 2.1 g ofcrude product. After recrystallization fromdiethylether/hexane and then methylene chloride/hexane one obtains1.1 g(28%) of trans-monoethyl 1,2-cyclopropanedicarboxylate,m/e=159 (M+H).

Part B:

To a solution of 297 mg (1.87 mmol) oftransmonoethyl1,2-cyclopropanedicarboxylate and 429 mg (2.8 mmol)N-hydroxybenzotriazole (HOBT) in 3 mL of anhydrousN,N-dimethylformamide(DMF) at 0° C. was added 394 mg (2.0 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC). After30 min. a solution of 591 mg(1.7 mmol) of product from Part A in 2 mLDMF and 171 mg(1.69 mmol) of N-methylmorpholine (NMM) was added. After2hours at 0° C., the reaction was stirred at RT overnight,poured intowater, extracted with ethyl acetate, washedwith water, 5% aq. citricacid, sat'd NaHCO₃, brine, driedover anhydride MgSO₄ and stripped toafford 771 mg of crudeproduct. This was chromatographed on silica gelusing5-20% methanol/methylene chloride to afford 670 mg (80%)ofcyclopropane carboxylic acid, 2- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!carbonyl!-,ethylester; m/e=490 (M+H).

Part C:

To a solution of 658 mg (1.32 mmol) of productfrom Part B in 5 mL of50:50 THF/water was added 66 mg(1.58 mmol) of lithium hydroxide. After19 hours, the THFwas removed in vacuo, the water washed with ethylacetate,acidified and reextracted with ethyl acetate. The secondorganiclayer was dried and stripped to afford 328 mg (54%)of the correspondingacid, m/e=462 (M+H).

Part D:

To a solution of 304 mg (0.66 mmol) of productfrom Part C, 151 mg (0.99mmol) HOBT in 2.2 mL DMF at 0° C.was added 139 mg (0.73 mmol) EDC. After30 min. at 0° C.,1.1 mL of conc. aqueous ammonia was added. Afterstirringat 0° C. for 2 hours and RT for 20 hours, the reaction waspouredinto brine and extracted with ethyl acetate. Afterwashing with sat'dNaHCO₃, brine, drying and stripping, oneobtains 141 mg of crude product.This was chromatographedon silica gel with 1-5% methanol/methylenechloride toafford 40 mg (13%) ofthe desired final product, m/e=561(M+H).

EXAMPLE 37 Preparation of trans-but-2-enediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*,2S*!

Part A:

To a solution of 137 mg (0.95 mmol) fumaric acidmonoethyl ester in 1 mLof DMF at 0° C. was added 183 mg(0.95 mmol) EDCl. After 15 minutes, asolution of 333 mg(0.95 mmol) of the compound of Example 34 Part E in 1mLDMF was added and the reaction stirred for 14 hours at RT.Ethylacetate was added and extracted with sat'd brine, 0.2 n HCl, sat'dNaHCO₃, dried and stripped to afford 0.32 g ofcrude product.Chromatography on silica gel using 0-50%ethyl acetate/hexane afforded0.26 g (58%) of but-2-enoicacid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-4-oxo-,1S- 1R*,2S*!!-, ethyl ester, m/e=476 (M+H).

Part B:

To a solution of 26.6 mg (0.56 mmol) of productfrom Part A in 3 mL of50:50 THF/water was added 34 mg(0.82 mmol) of lithium hydroxide and thereaction stirredat RT for 1 hour. The THF was removed in vacuo,theaqueous layer acidified with 1N HCl and extracted withethyl acetate.The organic layer was washed with brine,dried and stripped to afford 233mg (93%) of trans-but-2-enoicacid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-4-oxo-,1S- 1R*,2S*!-, m/e=448 (M+H).

Part C:

To a solution of 225 mg (0.50 mmol) of theproduct from Part B in 1 mL ofDMF was added 95 mg (0.50 mmol) EDC. After 15 minutes at RT, 0.50 mL ofconc.aqueous ammonia was added and the reaction stirred for15 hours.Ethyl acetate was added and washed with 0.2NHCl, brine, dried andstripped to afford 170 mg of crudeproduce. After chromatography onsilica gel using 0-40%methanol/methylene chloride, one obtains 50 mg(22%) oftrans-but-3-enediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*,2S*!-, m/e=447 (M+H).

EXAMPLE 38 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-HYDROXY-1-(phenylmethyl)propyl-2-methyl-,1S- l R*(2S*),2S*l -

Part A:

To a suspension of 24.7 g (0.22 mol) of itaconicanhydride in 100 mL ofanhydrous toluene at reflux under anitrogen atmosphere was addeddropwise over 30 minutes23.9 g (0.22 mol) of benzyl alcohol. Theinsoluble materialdissolved to provide a homogeneous solution whichwasrefluxed for 1.5 hours. The solution was cooled to RT,then in an icebath and the resulting white precipitatecollected by filtration toafford 24.8 g (51%) of 4-benzylitaconate.

Part B:

To a solution of 2.13 g (9.5 mmol) of the productfrom Part A in 12 mL ofmethylene chloride at 0° C. was added4.02 g (29.1 mmol) ofpara-methoxybenzyl alcohol, 605 mg(4.95 mmol) of N,N-dimethyl4-aminopyridine, 128 mg of N,N-dimethyl4-aminopyridine hydrochloridesalt and then 2.02 g(4.7 mmol) dicyclohexylcarbodiimide (DCC). Afterstirringan 0° C. for 1 hour and then RT for 2 hours, the precipitatewascollected and discarded. The filtrate was washed with0.5N HCl, sat'dNaHCO₃, dried and stripped to afford 4.76 gof crude product. This waschromatographed on silica gelusing 0-50% ethyl acetate/hexane to afford1.24 g of pure4'-methoxybenzyl-4-benzylitaconate.

Part C:

A solution of 1.24 g (3.65 mmol) of product fromPart B and 20 mg of(R,R)-Dipamp)cyclooctadienylrhodium!tetrafluoroborate in 30 mL ofmethanol was throughlydegassed, flushed with nitrogen and then hydrogenand thenstirred under 50 psig of hydrogen for 15 hours. Thesolution wasfiltered and stripped, dissolved in methylenechloride and washed withsat'd NaHCO₃, dried and strippedto afford 0.99 g of a brown oil. Thiswas then dissolved in40 mL of methylene chloride, 3 mL oftrifluoroacetic acidadded and the solution stirred at RT for 3.5 hours.Waterwas added and separated and the organic layer extractedwith sat'dNaHCO₃. The aqueous layer was acidified andreextracted with ethylacetate, separated and the organiclayer washed with brine, dried andstripped to afford 320 mg (50%) of 2(R)-methyl-4-benzylsuccinic acid.

Part D:

To a solution of 320 mg (1.44 mmol) of productfrom Part C and 314 mg(2.05 mmol) HOBT in DMF at 0° C. wasadded 303 mg (1.58 mmol) of EDC.After stirring for 30 minutes, a solution of 467 mg (1.34 mmol) of theproductfrom Example 34, Part E in 4 mL of DMF was added. Afterstirringfor 1 hour an 0° C. and 14 hours at RT, ethylacetate was added andwashed with sat'd NaHCO₃, 5% aqueouscitric acid, dried and stripped toafford 0.97 g of crudeproduct. This was chromatographed on silica gelusing0-10% ethyl acetate/hexane to afford 420 mg of purebutanoic acid,4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-3-methyl-4-oxo-,1S- 1R*(3S*),2S*!-, benzyl ester.

Part E:

A solution of 150 mg (0.27 mmol) of product fromPart D in 15 mL ofmethanol was hydrogenated over 10%palladium on carbon under 50 psighydrogen for 17 hours.The reaction was filtered and stripped to afford125 mg(100%) of butanoic acid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-3-methyl-4-oxo-,1S- 1R*(3S*),2S*!-.

Part F:

To a solution of 125 mg (0.27 mmol) of productfrom Part E and 65 mg(0.42 mmol) of HOBT in 5 mL of DMF at0° C. was added 59 mg (0.31 mmol)of EDC. After 30 min. at0° C., 1 mL of conc. aqueous ammonia was added.Afterstirring at 0° C. for 2 hours and RT for 15 hours, ethylacetate wasadded and washed with sat'd NaHCO₃, 5% aqueouscitric acid, dried andstripped to afford 90 mg of crudeproduct. This was recrystallized fromethyl acetate/hexaneto afford 40 mg (32%) of pure butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl,1S- 1R*(2S*),2S*!-.

EXAMPLE 39 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl,1S- 1R*(2R*),2S*!-

Part A:

A solution of 1.41 g (4.1 mmol) of 4-methoxybenzyl4-benzylitaconate and25 mg of (S,S-Dipamp)cyclooctadienylrhodium!tetrafluoroborate in 20 mLofmethanol was thoroughly degassed, flushed with nitrogen andthenhydrogen and then stirred under 40 psig hydrogen for72 hours. Thesolution was filtered and concentrated toprovide 1.34 g of a brown oil.This was dissolved in 40 mLof methylene chloride and 3 mL oftrifluoroacetic acid wasadded. After stirring for 4 hours, water wasadded,separated and the organic layer extracted with sat'dNaHCO₃. Theaqueous layer was separated, reacidified,extracted with ethyl acetatewhich was separated, washedwith brine, dried and stripped to afford 440mg of 2(S)-methyl-4-benzylsuccinic acid.

Part B:

To a solution of 440 mg (1.98 mmol) of theproduct from Part A and 437 mg(2.86 mmol) of HoBT in 9 mLof DMF at 0° C. was added 427 mg (2.23 mmol)of EDCl. After30 minutes at 0° C., a solution of 653 mg (1.87 mmol) oftheproduct from Example 34, Part E in 3 mL DMF was added.After 1 hour at0° C. and 15 hours at RT, ethyl acetate wasadded, extracted with sat'dNaHCO₃, 5% aqueous citric acid,dried and concentrated to afford 0.98 gof crude product.Chromatography on silica gel using 0-10% ethylacetateafforded 610 mg (59%) of pure butanoic acid, 4- 3-(1,1-dimethylethyl)-amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-3-methyl-4-oxo-,1S- 1R*(3R*),2S*!, benzyl ester.

Part C:

A solution of 310 mg (0.56 mmol) of the productfrom Part B in 20 mL ofmethanol was hydrogenated over 20 mg of 10% palladium on carbon under 50psig hydrogen for 19 hours. The solution was filtered and concentratedtoafford 220 mg (85%) of butanoic acid, 4- 3-(1,1-dimethylethyl)-amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-3-methyl-4-oxo-,1S- 1R*(3R*),2S*!.

Part D:

To a solution of 190 mg (0.41 mmol) of theproduct from Part C and 90 mg(0.58 mmol) HOBT in 5 mL ofDMF at 0° C., was added 88 mg (0.46 mmol) ofEDC. After 30 minutes at 0° C., 2 mL of conc. aqueous ammonia wasadded.After 1 hour at 0° C. and 15 hours at RT, ethyl acetate wasadded,washed with sat'd NaHCO₃, 5% aqueous citric acid,dried and concentratedto afford crude product.Recrystallization from ethyl acetate/hexaneafforded 20 mg(11%) of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-methyl,1S- 1R*(2R*),2S*!.

EXAMPLE 40 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-3-methyl-,1S- 1R*(3S*),2S*!-

Part A:

In a similar manner to the procedure used above,p-methoxybenzyl alcoholwas reacted with itaconic anhydridein refluxing toluene to provide4-(p-methoxybenzyl)itaconate.

Part B:

To a solution of 3.30 g (13.2 mmol) of theproduct from Part A in 17 mLof toluene, was added 2.08 g(13.7 mmol) of 1,8-diazabicyclo5.40!undec-7-ene and then2.35 g (13.7 mmol) of benzyl bromide. After 2hours, thesolution was filtered and the filtrate washed withsat'dNaHCO₃, 3N HCl, brine, dried and concentrated to afford3.12 g of anoil. After chromatography on silica gel using0-5% ethyl acetate/hexaneone obtains 2.19 g (49%) of benzyl4-(4-methoxybenzyl)itaconate.

Part C:

A solution of 1.22 g (3.6 mmol) of product fromPart B and 150 mg of((R,R-Dipamp))cyclooctadienylrhodium!tetrafluoroborate in 15 mLofmethanol was thoroughly degassed, flushed with nitrogen andthenhydrogen and hydrogenated under 50 psig for 16 hours.The solution wasfiltered and concentrated to afford 1.2 gof a brown oil. This wasdissolved in 5 mL of methylenechloride and 5 mL of toluene and 3 mL oftrifluoroaceticacid was added. After 4 hours, the solvents wereremovedin vacuo, the residue dissolved in methylene chloride,which wasthen extracted with sat'd NaHCO₃. Afterseparation, the aqueous layer wasacidified, reextractedwith methylene chloride which was then driedandconcentrated to afford 470 mg (60%) of3(R)-methyl-4-benzylsuccinicacid.

Part D:

To a solution of 470 mg (2.11 mmol) of productfrom Part C and 463 mg(3.03 mg) of HOBT in 5 mL of DMF at0° C. was added 451 mg (2.35 mmol) ofEDC. After 30 min. at0° C., a solution of 728 mg (2.08 mmol) of theproduct fromExample 34, Part E in 3 mL of DMF was added. Afterstirringat 0° C. for 1 hour and 15 hours at RT, ethylacetate was added andextracted with sat'd NaHCO₃, 5%aqueous citric acid, brine, dried andconcentrated to give930 mg of crude product chromatography on silica gelusing0-10% ethyl acetate/hexane one obtains 570 mg (50%) ofbutanoicacid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-2-methyl-4-oxo-,1S- 1R*(2S*),2S*!-, benzyl ester.

Part E:

The product was hydrogenated in methanol using10% palladium on carbonunder 40 psig of hydrogen to affordbutanoic acid, 4- 3-(1,1-dimethylethyl)amino!carbonyl!3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!amino!-2-methyl-4-oxo-,1S- 1R*(2S*),2S*!-.

Part F:

To a solution of 427 mg (0.92 mmol) of productfrom Part E and 210 mg(1.37 mmol) in 3 mL of DMF at 0° C.was added 196 mg (1.02 mmol) of EDC.After 30 min. at 0° C.,2 mL of conc. aqueous ammonia was added. After 1hour at0° C. and 15 hours at RT, ethyl acetate was added andthenextracted with sat'd NaCHO₃, brine, dried and concentratedto affordcrude product. Recrystallization from ethylacetate/hexane afforded 50 mg(12%) of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-3-methyl-,1S- 1R*(3S*),2S*!-.

EXAMPLE 41 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-3-methyl -, 1S- 1R*(3R*),2S*!-

This was prepared in an identical manner to theprevious example exceptthat the asymmetric hydrogenationstep was done in the presence of((S,S-dipamp)cyclooctadienyl)rhodium!-tetrafluoroborate ascatalyst.

EXAMPLE 42 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*(2S*,3R*),2S*!!, and 1S- 1R*(2R*,3S*),2S*!!

Part A:

To a solution of 863 mg (5.91 mmol) of meso-2,3-dimethylsuccinicacid in7 mL of DMF at RT was added 1.13 g(5.91 mmol) of EDC. After 15 minutes,a solution of 2.07 g(5.91 mmol) of the product from Example 34, Part Eand 1.4 mL of pyridine in 7 mL of anhydrous methylene chloride wasadded.After 11 hours, ethyl acetate was added and washedwith 0.2N HCl, brine,dried and concentrated to afford2.73 g (97%) of a 1:1 mixture ofdiastereomeric acids.

Part B:

To a solution of 1.45 g (3.04 mmol) of the 1:1 mixture from Part A and613 mg (4.51 mmol) of HOBT in 10 mLof DMF at 0° C. was added 635 mg(3.31 mmol) of EDC. After30 minutes at 0° C., 5 mL of conc. aqueousammonia was added.After 1 hour at 0° C. and 14 hours at RT, ethylacetate wasadded, washed with 0.2N HCl, sat'd NaCHO₃, brine, driedandconcentrated to afford 0.64 g (44%) of a 1:1 mixture ofamides.

These were separated on a Whatman 10 micronpartisil column using 8%-14%isopropanol/-methylenechloride. The first isomer to elute was identifiedasbutanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*(2R*,3S*),2S*!,m/e/=477 (M+H).

The second isomer to elute was identified asbutanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-,1S- 1R*(2S*,3R*),2S*!, m/e=477 (M+H).

EXAMPLE 43 Preparation of pentanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl-3,3-dimethyl-,1S- 1R*,2S*!

Part A:

To a solution of 232 mg (0.66 mmol) of theproduct from Example 34, PartE and 98 mg (1.2 mmol) ofpyridine in 2 mL of methylene chloride wasadded 95 mg(0.66 mmol) of 3,3-dimethylglutaric anhydride at RT. After15hours, ethyl acetate was added, washed with IN HCl,brine, dried andconcentrated to afford 261 mg of crudeproduct. Chromatography on silicagel using 5-20%methanol/methylene chloride afforded 108 mg of acid,m/e=492 (M+H).

Part B:

To a solution of 92 mg (0.19 mmol) of productfrom Part A and 38 mg (0.28mmol) HOBT in 0.5 mL DMF at 0° C.was added 36 mg (0.19 mmol) of EDC.After 30 minutes at0° C., 0.25 mL of conc. aqueous ammonia was added.After 1 hour at 0° C. and 16 hours at RT, ethyl acetate was added,washedwith 0.2N HCl, sat'd NaHCO₃, brine, dried andconcentrated to afford 72mg of crude product. This waspassed through a one-inch column of basicalumina with 10%methanol/methylene chloride to afford 53 mg ofdesiredproduct, m/e=491 (M+H).

EXAMPLE 44 Preparation of butanediamide, N- 3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2,3-dimethyl-1S- 1R*(2R*,3S*),2S*!! (Isomer #1) and Preparation of butanediamide, N-3-(1,1-dimethylethyl)amino!carbonyl!(3-methylbutyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2,3-dimethyl-1S- 1R*(2R*,3S*),2S*!! (Isomer #2)

Part A:

To a solution of 1.47 g (4.20 mmol) of theproduct from Example 34, PartE and 1.4 mL of pyridine in 9 mL of methylene chloride at RT was added538 mg (4.20 mmol)of 2,2-dimethylsuccinic anhydride. After 15 hours,ethylacetate was added and washed with 0.2N HCl, brine, driedandconcentrated to afford 1.87 g of crude product (approx.3:1 mixture ofisomers).

Part B:

To a solution of 1.85 g (3.9 mmol) of crudeproduct from Part A and 887mg (5.8 mmol) of HOBT in 10 mLof DMF at 0° C. was added 809 mg (4.2mmol) EDC. After 30 minutes at 0° C., 6 mL of conc. aqueous ammonia wasadded.After 1 hour at 0° C. and 15 hours at RT, ethyl acetate wasadded,washed with 0.2N HCl, sat'd NaHCO₃, brine, driedand concentrated toafford 923 mg of crude product. Thetwo isomers were separated on aWhatman Partisil 5 columnusing 8-14% isopropanol/methylene chloride. Themajorisomer was identified as Isomer #1, m/e=477 (M+H).

The minor isomer was identified as Isomer #2, m/e=477 (M+H).

EXAMPLE 45

This example illustrates the procedure utilizedto prepare compoundswherein the stereochemistry about thehydroxyl group is (S).

Part A:

A solution of3(S)-(1,1-dimethylethoxycarbonyl)amino-1,2-(R)-epoxy-4-phenylbutane(1.00 g, 3.80 mmol) andisobutylamine (5.55 g, 76 mmol, 20 equiv.) in 10mL ofisopropyl alcohol was warmed to 60° C. for 1 hour. Thesolution wascooled to room temperature and concentrated invacuo and the residuerecrystallized from hexane/methylenechloride to give 0.93 g, 73% of2(S),3(S)!-N- 3-(1,1-dimethylethyl)carbamoyl!amino!!-2-hydroxy-4-phenylbutyl!N-(3-methylbutyl)!amine, mp 91.3°-93.0° C.

Part B:

The product from Part A (46.3 mg, 0.14 mmol) wasdissolved in a mixtureof 5 mL of tetrahydrofuran and 2 mLof methylene chloride and treatedwith tert-butylisocyanate(136.4 mg, 1. 376 mmol) via syringe. Thesolution wasstirred at room temperature for 0.5 hour and then thesolventwas removed in vacuo. The product, TLC on SiO₂,1:1 hexane:ethyl acetatehad Rf=0.74 and was useddirectly in the next step without furtherpurification.

Part C:

The crude product from Part B was taken up in 10 mL of 4N hydrochloricacid in dioxane and stirred at roomtemperature for 0.25 hours. Thesolvent and excesshydrochloric acid was removed in vacuo whereupontheproduct crystallized. The solid was isolated by filtrationwashed withacetone and dried in vacuo to 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino-2(S)-hydroxy-1(S)-(phenylmethyl)propylaminehydrochloride.

Part D:

A solution of N-Cbz-L-asparagine (225.5 mg, 0.847 mmol) andN-hydroxybenzotriazole (182.9 mg, 1.21 mmol) wasdissolved in 2 mL ofdimethylformamide and cooled to 0° C.and then treated with EDC (170.2mg, 0.898 mmol) for 10 minutes. This mixture was then treated with 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino-2(S)-hydroxy-1(S)-(phenylmethyl)propylaminehydrochloride.(300.0 mg, 0.807 mmol) followed by N-methylmorpholine(90.0mg, 0.888 mmol) via syringe. The solution was stirredat room temperaturefor 16 hours and then poured into 20 mLof rapidly stirring 60% saturatedaqueous sodiumbicarbonate solution whereupon a white precipitateformed.The solid was isolated by filtration, washed withsaturatedaqueous sodium bicarbonate solution, water, 5% aqueouscitricacid solution, water and then dried in vacuo to give319 mg, 68% ofbutanediamide, N¹ - 3-(1,1-dimethylethyl)amino!carboyl!(2-methylpropyl)amino!-2(S)-hydroxy-1(S)-(phenylmethyl)propyl!-2(S)-(benzyloxycarbonyl)amino! mp 139°-141° C., MH⁺ m/z=584.

EXAMPLE 46

Following the above general procedures butsubsituting an acid chlorideor an hydride for theisocyanate or similar starting material, thecompoundsshown in Tables 16A and 16B were

                  TABLE 16A    ______________________________________     ##STR170##    Entry        XR.sup.4       A    ______________________________________    1            CH.sub.2 C(CH.sub.3).sub.3                                CbzAsn    2            CH.sub.2 C(CH.sub.3).sub.3                                QAsn    3            CH.sub.2 C(CH.sub.3).sub.3                                Cbz-tBugly    ______________________________________

                  TABLE 16B    ______________________________________     ##STR171##    X(R.sup.4) (R.sup.5)    ______________________________________     ##STR172##     ##STR173##     ##STR174##     ##STR175##     ##STR176##     ##STR177##     ##STR178##     ##STR179##     ##STR180##     ##STR181##     ##STR182##     ##STR183##    ______________________________________

EXAMPLE 47

Following the above general procedures bunsubstituting a chloroformateor pyrocarbonate for theisocyantae or similar starting material, thecompoundsshown in Table 17 were

                  TABLE 17    ______________________________________     ##STR184##    Entry         XHR.sup.4    A    ______________________________________    1             O.sup.t Bu   CbzAsn    2             O.sup.t Bu   Cbz    3             O.sup.t Bu   QAsn    4             O.sup.t Bu   Cbz-tBugly    ______________________________________

EXAMPLE 48

The compounds of the present invention areeffective HIV proteaseinhibitors. Utilizing an enzymeassay as described below, the compoundsset forth in theexamples herein disclosed inhibited the HIV enzyme.Thepreferred compounds of the present invention and theircalculated IC₅₀(inhibiting concentration 50%, i.e., theconcentration at which theinhibitor compound reducesenzyme activity by 50%) values are shown inTable 18. Theenzyme method is described below. The substrate is2-aminobenzoyl-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂.The positivecontrol isMVT-101 (Miller, M. et al, Science, 246, 1149 (9189)! The assayconditions are as follows:

Assay buffer:

20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS

The above described substrate is dissolved inDMSO, then diluted 10 foldin assay buffer. Finalsubstrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to afinal enzymeconcentration of 12.3 nanomolar, based on amolecular weight of 10,780.

The final concentration of DMSO is 14% and thefinal concentration ofglycerol is 18%. The test compoundis dissolved in DMSO and diluted inDMSO to 10× the testconcentration; 10 μl of the enzyme preparation isadded, thematerials mixed and then the mixture is incubated atambienttemperature for 15 minutes. The enzyme reaction isinitiated by theaddition of 40 μl of substrate. Theincrease in fluorescence is monitoredat 4 time points (0,8, 16 and 24 minutes) at ambient temperature. Eachassayis carried out in duplicate

                  TABLE 18    ______________________________________    Compound                IC.sub.50 (nanomolar)    ______________________________________    1.    Butanediamide, N.sup.1 - 3-   (2,2-                                  21     nM          dimethyl)propyl!carbonyl!(3-          methylbutyl)amino!-2-hydroxy-1-          (phenylmethyl)propyl!-2- (2-          quinolinylcarbonyl)amino!-,           1S- 1R*(2R*),2S*!!    2.    Butanediamide, N.sup.1 - 3-                                  696    nM            butylcarbonyl!(cyclohexylmethyl)-          amino!-2-hydroxy-1-(phenylmethyl)          propyl!-2- (phenylmethyloxy)-          carbonyl)amino!-,  1S- 1R*(2R*),2S*!!    3.    Carbamic acid,  3-  4-amino-1,4-                                  1.6    nM          dioxo-2- (phenylmethyloxy)carbonyl!          amino!butyl!amino!-2-hydroxy-4-          phenylbutyl!(phenylmethyl)-,          butyl ester,  2R- 2R*,3S*(S*)!!    ______________________________________

EXAMPLE 48

The effectiveness of the compounds listed inTable 19 were determined inthe above-described enzymeassay and in a CEM cell assay.

The HIV inhibition assay method of acutelyinfected cells is an automatedtetrazolium basedcolorimetric assay essentially that reported by Pauwlesetal, J. Virol. Methods 20, 309-321 (1988). Assays wereperformed in96-well tissue culture plates. CEM cells, aCD4⁺ cell line, were grown inRPMI-1640 medium (Gibco)supplemented with a 10% fetal calf serum andwere thentreated with polybrene (2 μg/ml). An 80 μl volume ofmediumcontaining 1×10⁴ cells was dispensed into each well ofthe tissueculture plate. To each well was added a 100 μlvolume of test compounddissolved in tissue culture medium(or medium without test compound as acontrol) to achievethe desired final concentration and the cellswereincubated at 37° C. for 1 hour. A frozen culture of HIV-1 wasdiluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀ =the dose of virus that infects 50%of cells in tissue culture),and a 20 μL volume of the virussample (containing 1000 TCID₅₀ of virus)was added to wellscontaining test compound and to wells containingonlymedium (infected control cells). Several wells receivedculturemedium without virus (uninfected control cells).Likewise, the intrinsictoxicity of the test compound wasdetermined by adding medium withoutvirus to several wellscontaining test compound. In summary, the tissuecultureplates contained the following

    ______________________________________    Cells             Drug    Virus    ______________________________________    1.      +             -       -    2.      +             +       -    3.      +             -       +    4.      +             +       +    ______________________________________

In experiments 2 and 4 the finalconcentrations of test compounds were 1,10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxylnosine(ddI)was included as a positive drug control. Test compoundsweredissolved in DMSO and diluted into tissue culturemedium so that thefinal DMSO concentration did not exceed1.5% in any case. DMSO was addedto all control wells atan appropriate concentration.

Following the addition of virus, cells wereincubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 ifdesired. On day 7, post-infection, the cells ineach wellwere resuspended and a 100 μl sample of each cell suspensionwasremoved for assay. A 20 μL volume of a 5 mg/ml solutionof3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltenrazoliumbromide (MTT) wasadded to each 100 μL cell suspension, andthe cells were incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolicallyreduced by living cells resulting in the production inthecell of a colored formazan product. To each sample wasadded 100 μl of10% sodium dodecylsulfate in 0.01N HCl tolyse the cells, and sampleswere incubated overnight. Theabsorbance at 590 nm was determined foreach sample using aMolecular Devices microplate reader. Absorbancevalues foreach set of wells is compared to assess viralcontrolinfection, uninfected control cell response as well astestcompound by cytotoxicity and antiviral

                  TABLE 19    ______________________________________    Compound              Inhibition    ______________________________________    1.    Butanediamide, N.sup.1 - 3-   (2,2-                              100%          dimethyl)propyl!carbonyl!          (3-methylbutyl)amino!-2-hydroxy-          1-(phenylmethyl)propyl!-2- (2-          quinolinylcarbonyl)amino!-,           1S- 1R*(2R*),2S*!!    ______________________________________

Following the procedures set forth above, thefollowing compounds werealso prepared:

Carbamic acid, 3- (4-amino-1,4-dioxo-2-(2-quinolinylcarbonyl)amino!butyl!amino!-2-hydroxy-4phenylbutyl!(4-fluorophenyl)methyl!-, 1,1-dimethylethylester, 2R- 2R*,3S*(S*)!!-

Carbamic acid, 3- (4-amino-1,4-dioxo-2-(2-quinolinylcarbonyl)amino!butyl!amino!-2-hydroxy-4-phenylbutyl!(3-methylbutyl)!-, 1,1-dimethylethyl ester, 2R- 2R*,3S*(S*)!!-

Carbamic acid, 3- (4-amino-1,4-dioxo-2-(2-quinolinylcarabonyl)amino!butyl!amino!-2-hydroxy-4-phenylbutyl!(2-methylpropyl)!-, 1,1-dimethylethyl ester, 2R- 2R*,3S*(S*)!!-

Carbamic acid, 3- (4-amino-1,4-dioxo-2-(2-quinolinylcarbonyl)amino!butyl!amino!-2-hydroxy-4-phenylbutyl!(4-pyridylmethyl)!-, 1,1-dimethylethyl ester, 2R- 2R*,3S*(S*)!!-

Utilizing generally the procedures set forthabove, the compounds shownin Tables 20-48 could beprepared. It is contemplated that such compoundswillinhibit retroviral proteases.

As stated above, the procedures see forth hereincould be utilized toprepare the compounds shown in Tables20-46 set forth

                                      TABLE 20    __________________________________________________________________________     ##STR185##    Entry No.          R              R.sup.3        R.sup.4    __________________________________________________________________________     1    Cbz.sup.a      CH.sub.3       n-Butyl     2    Cbz            i-Butyl        CH.sub.3     3    Cbz            i-Butyl        n-Butyl     4    Q.sup.b        i-Butyl        n-Butyl     5    Cbz            i-Propyl       n-Butyl     6    Q              i-Propyl       n-Butyl     7    Cbz            C.sub.6 H.sub.5                                        n-Butyi     8    Cbz                          ##STR186##    n-Butyl     9    Cbz                          ##STR187##    n-Butyl    10    Q                          ##STR188##    n-Butyl    11    Cbz                          ##STR189##    n-Butyl    12    Cbz            i-Butyl        n-Propyl    13    Cbz            i-Butyl        CH.sub.2 CH(CH.sub.3).sub.2    14    Cbz                          ##STR190##    n-Butyl    15    Cbz                          ##STR191##    i-Propyl    16    Cbz                          ##STR192##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2    17    Cbz            i-Butyl        CH.sub.2 CH.sub.3    18    Cbz            i-Butyl        CH(CH.sub.3).sub.2    19    Cbz            i-Butyl                                         ##STR193##    20    Q              i-Butyl                                         ##STR194##    21    Cbz                          ##STR195##    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    22    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        CH(CH.sub.3).sub.2    23    Q              i-Butyl        CH(CH.sub.3).sub.2    24    Cbz            i-Butyl        C(CH.sub.3).sub.3    25    Q              i-Butyl        C(CH.sub.3).sub.3    26    Cbz                          ##STR196##    C(CH.sub.3).sub.3    27    Q                          ##STR197##    C(CH.sub.3).sub.3    28    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    29    Q              (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    30    Cbz            CH.sub.2 C6H.sub.5                                        C(CH.sub.3).sub.3    31    Q              CH.sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    32    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    33    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    34    Cbz            n-Butyl        C(CH.sub.3).sub.3    35    Cbz            n-Pentyl       C(CH.sub.3).sub.3    36    Cbz            n-Hexyl        C(CH.sub.3).sub.3    37    Cbz                          ##STR198##    C(CH.sub.3).sub.3    38    Cbz            CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    39    Q              CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    40    Cbz                          ##STR199##    C(CH.sub.3).sub.3    41    Cbz            CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3                                        C(CH.sub.3).sub.3    42    Cbz                          ##STR200##    C(CH.sub.3).sub.3    43    Cbz                          ##STR201##    C(CH.sub.3).sub.3    44    Cbz            (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    45    Q              (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    46    Cbz            (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    47    Q              (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    48    Q                          ##STR202##    C(CH.sub.3).sub.3    49    Q                          ##STR203##    C(CH.sub.3).sub.3    50           ##STR204##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    51           ##STR205##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    52           ##STR206##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    53           ##STR207##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    54           ##STR208##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    55           ##STR209##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    56           ##STR210##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    57           ##STR211##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    58           ##STR212##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    59           ##STR213##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    60           ##STR214##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    61           ##STR215##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    62           ##STR216##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    63           ##STR217##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    64           ##STR218##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    65           ##STR219##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    66           ##STR220##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    67           ##STR221##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    68           ##STR222##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    69           ##STR223##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    __________________________________________________________________________     .sup.a benzyloxycarbonyl     .sup.b 2quinolinylcarbonyl

                                      TABLE 21    __________________________________________________________________________     ##STR224##    Entry         A                   R.sup.3    R.sup.4    __________________________________________________________________________     1   CbzVal              i-amyl     tBu     2   CbzLeu              i-amyl     t-Bu     3   CbzIle              i-amyl     t-Bu     4   AcD-homo-Phe        i-Bu       n-Bu     5   QuiOrn(γ-Cbz)                              ##STR225##                                        t-Bu     6   CbzAsn              CH.sub.2 CHCH.sub.2                                        t-Bu     7   Acetyl-t-BuGly      i-amyl     t-Bu     8   Acetyl-Phe          i-amyl     t-Bu     9   Acetyl-Ile          i-amyl     t-Bu    10   Acetyl-Leu          i-amyl     t-Bu    11   Acetyl-His          i-amyl     t-Bu    12   Acetyl-Thr          i-amyl     t-Bu    13   Acetyl-NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    14   CbzAsn              i-amyl     t-Bu    15   CbzAla              i-amyl     t-Bu    16   CbzAla              i-amyl     t-Bu    17   Cbz-beta-cyanoAla   i-amyl     t-Bu    18   Cbz-t-BuGly         i-amyl     t-Bu    19   Q-t-BuGly           i-amyl     t-Bu    20   QSCH.sub.3 Cys      i-amyl     t-Bu    21   CbzSCH.sub.3 Cys    i-amyl     t-Bu    22   QAsp                i-amyl     t-Bu    23   Cbz(NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    24   CbzEtGly            i-amyl     t-Bu    25   CbzPrGly            i-amyl     t-Bu    26   CbzThr              i-amyl     t-Bu    27   QPhe                i-amyl     t-Bu    28   CbzPhe              i-amyl     t-Bu    29   Cbz NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    30   Q NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    __________________________________________________________________________

                  TABLE 22    ______________________________________     ##STR226##    Entry            R.sup.1    ______________________________________    1                CH.sub.2 SO.sub.2 CH.sub.3    2                (R)CH(OH)CH.sub.3    3                CH(CH.sub.3).sub.2    4                (R,S)CH.sub.2 SOCH.sub.3    5                CH.sub.2 SO.sub.2 NH.sub.2    6                CH.sub.2 SCH.sub.3    7                CH.sub.2 CH(CH.sub.3).sub.2    8                CH.sub.2 CH.sub.2 C(O)NH.sub.2    9                (S)CH(OH)CH.sub.3    10               CH.sub.2 CCH    11               CH.sub.2 CCH.sub.2    ______________________________________

                  TABLE 23    ______________________________________     ##STR227##    Entry    R.sup.2        A    ______________________________________     1       n-Bu           CbzAsn     2       cyclohexylmethyl                            CbzAsn     3       n-Bu           Boc     4       n-Bu           Cbz     5       C.sub.6 H.sub.5 CH.sub.2                            Boc     6       C.sub.6 H.sub.5 CH.sub.2                            Cbz     7       C.sub.6 H.sub.5 CH.sub.2                            benzoyl     8       cyclohexylmethyl                            Cbz     9       n-Bu           QAsn    10       cyclohexylmethyl                            QAsn    11       C.sub.6 H.sub.5 CH.sub.2                            CbzIle    12       C.sub.6 H.sub.5 CH.sub.2                            QIle    13       C.sub.6 H.sub.5 CH.sub.2                            Cbz-t-BuGly    14       C.sub.6 H.sub.5 CH.sub.2                            Q-t-BuGly    15       C.sub.6 H.sub.5 CH.sub.2                            CbzVal    16       C.sub.6 H.sub.5 CH.sub.2                            QVal    17       2-naphthylmethyl                            CbzAsn    18       2-naphthylmethyl                            QAsn    19       2-naphthylmethyl                            Cbz    20       n-Bu           CbzVal    21       n-Bu           QVal    22       n-Bu           QIle    23       n-Bu           Cbz-t-BuGly    24       n-Bu           Q-t-BuGly    25       p-F(C.sub.6 H.sub.4)CH.sub.2                            QAsn    26       p-F(C.sub.6 H.sub.4)CH.sub.2                            Cbz    27       p-F(C.sub.6 H.sub.4)CH.sub.2                            CbzAsn    28       C.sub.6 H.sub.5 CH.sub.2                            Cbz-propargylglycine    29       C.sub.6 H.sub.5 CH.sub.2                            Q-propargylglycine    30       C.sub.6 H.sub.5 CH.sub.2                            acetyl-proparglyglycine    31       i-Bu           CbzAsn    ______________________________________

                  TABLE 24    ______________________________________     ##STR228##    R.sup.3          R.sup.4    ______________________________________    CH.sub.2 CH(CH.sub.3).sub.2                     C(CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR229##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR230##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR231##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR232##    ______________________________________

                                      TABLE 25    __________________________________________________________________________     ##STR233##    Entry        R                        R.sub.1    __________________________________________________________________________         ##STR234##              CH.sub.3    2         ##STR235##              CH.sub.3    3         ##STR236##              CH(CH.sub.3).sub.2    4         ##STR237##              CH(CH.sub.3).sub.2    5         ##STR238##              C(CH.sub.3).sub.3    6         ##STR239##              CH.sub.3    7         ##STR240##              CH.sub.3    8         ##STR241##              CH.sub.3    9         ##STR242##              CH.sub.3    10         ##STR243##              CH.sub.3    11         ##STR244##              CH.sub.3    12         ##STR245##              CH.sub.3    13         ##STR246##              CH.sub.3    14         ##STR247##              CH.sub.3    15         ##STR248##    16         ##STR249##    __________________________________________________________________________

                  TABLE 26    ______________________________________     ##STR250##    R.sup.1         R.sup.1'                 R.sup.1"  R    ______________________________________    H    H       H                            ##STR251##    H    H       H                            ##STR252##    H    CH.sub.3                 H                            ##STR253##    H    CH.sub.3                 CH.sub.3                            ##STR254##    H    H       CO.sub.2 CH.sub.3                            ##STR255##    H    H       H                            ##STR256##    H    H       H                            ##STR257##    H    H       CONH.sub.2                           Cbz    H    H       CONH.sub.2                           2-quinolinylcarbonyl    ______________________________________

                  TABLE 27    ______________________________________     ##STR258##    R                 R'          X    ______________________________________    R = H             R' = H      X = H    R = Me            R' = Me     X = H    R = H             R' = Me     X = H    R = Me            R' = Me     X = F    R = H             R' = Me     X = F    R = Cbz           R' = Me     X = H    R = H             R' = Bz     X = H    R + R' = pyrrole*             X = H    ______________________________________     *lle in place of tbutylglycine

                  TABLE 28    ______________________________________     ##STR259##     ##STR260##     ##STR261##    ______________________________________

                  TABLE 29    ______________________________________     ##STR262##    Acyl Group (R)    ______________________________________    benzyloxycarbonyl    tert-butoxycarbonyl    acetyl    2-quinoylcarbonyl    phenoxyacetyl    benzoyl    methyloxaloyl    pivaloyl    trifluoracetyl    bromoacetyl    hydroxyacetyl    morpholinylacetyl    N,N-dimethylaminoacetyl    N-benzylaminoacetyl    N-phenylaminoacetyl    N-benzyl-N-methylaminoacetyl    N-methyl-N-(2-hydroxyethyl)aminoacetyl    N-methylcarbamoyl    3-methylbutyryl    N-isobutylcarbamoyl    succinoyl (3-carboxypropionyl)    carbamoyl    N-isobutylamino acetyl    N,N-diethylamino acetyl    N-(2-methoxyethyl)aminoacetyl    N-(S-α-methylbenzyl)aminoacetyl    N-(R-α-methylbenzyl)amino acetyl    N-(S-2-tetralin)amino acetyl    N-(R-2-teralin)amino acetyl    N-pyrrolidinylacetyl    N-methyl-N-(2-pyridylethyl)amino acetyl    N-tetrahydroisoquinolylaminoacetyl    N-p-methoxybenzylamino acetyl    ______________________________________

                  TABLE 30    ______________________________________     ##STR263##    R'    ______________________________________    CH.sub.3    CH.sub.3 CH.sub.2    CH.sub.3 CH.sub.2 CH.sub.2    PhCH.sub.2 CH.sub.2    PhCH.sub.2    Ph    (CH.sub.3).sub.2 CH    HOCH.sub.2 CH.sub.2     ##STR264##     ##STR265##     ##STR266##    CH.sub.2CHCH.sub.2    ______________________________________

                  TABLE 31    ______________________________________     ##STR267##    R                  R.sub.1    ______________________________________    CH.sub.3           CH(CH.sub.3).sub.2    CH.sub.3           C(CH.sub.3).sub.3    ______________________________________

                                      TABLE 32    __________________________________________________________________________     ##STR268##    R.sup.1 R.sup.30               R.sup.31                   R.sup.32                       X' R.sup.33                                  R.sup.34    __________________________________________________________________________    H       H  H   H   N  H       H    H       H  H   H   O  H       --    H       H  H   H   O  CH.sub.3                                  --    CH.sub.3            H  H   H   N  H       H    CH.sub.3            H  H   H   O  H       --    H       H  CH.sub.3                   H   N  H       H    H       H  CH.sub.3                   H   O  H       --    CH.sub.3            CH.sub.3               H   H   N  H       H    CH.sub.3            CH.sub.3               H   H   O  H       --    CH.sub.3            CH.sub.3               H   H   O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    H       H  CH.sub.3                   CH.sub.3                       N  H       H    H       H  CH.sub.3                   CH.sub.3                       O  H    H       H  CH.sub.3                   CH.sub.3                       O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    CH.sub.3            H  CH.sub.3                   H   N  H       H    CH.sub.3            H  CH.sub.3                   H   N  H       CH.sub.3    CH.sub.3            H  CH.sub.3                   H   N  CH.sub.3                                  CH.sub.3    CH.sub.3            H  CH.sub.3                   H   O  H       --    CH.sub.3            H  CH.sub.3                   H   N  H       CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3    OH      H  H   H   N  H       H    OH      H  H   H   O  H       --    H       H  OH  H   N  H       H    H       H  OH  H   O  H       --    CH.sub.2            H  H   H   N  H       H    CH.sub.2 C(O)NH.sub.2            H  H   H   N  H       H    CH.sub.2 C(O)NH.sub.2            H  H   H   O  H       --    CH.sub.2 C(O)NH.sub.2            H  H   H   O  CH.sub.3                                  --    CH.sub.2 Ph            H  H   H   N  H       H    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  H       H    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  H       --    CH.sub.3            H  CH.sub.3                   CH.sub.3                       O  H       CH.sub.3    CH.sub.3            H  CH.sub.3                   CH.sub.3                       N  CH.sub.3                                  CH.sub.3    __________________________________________________________________________

                  TABLE 33    ______________________________________     ##STR269##     ##STR270##     ##STR271##     ##STR272##    ______________________________________

                                      TABLE 34    __________________________________________________________________________     ##STR273##    Entry No.          R              R.sup.3        R.sup.4    __________________________________________________________________________     1    Cbz.sup.a      CH.sub.3       n-Butyl     2    Cbz            i-Butyl        CH.sub.3     3    Cbz            i-Butyl        n-Butyl     4    Q.sup.b        i-Butyl        n-Butyl     5    Cbz            i-Propyl       n-Butyl     6    Q              i-Propyl       n-Butyl     7    Cbz            C.sub.6 H.sub.5                                        n-Butyl     8    Cbz                          ##STR274##    n-Butyl     9    Cbz                          ##STR275##    n-Butyl    10    Q                          ##STR276##    n-Butyl    11    Cbz                          ##STR277##    n-Butyl    12    Cbz            i-Butyl        n-Propyl    13    Cbz            i-Butyl        CH.sub.2 CH(CH.sub.3).sub.2    14    Cbz                          ##STR278##    n-Butyl    15    Cbz                          ##STR279##    i-Propyl    16    Cbz                          ##STR280##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2    17    Cbz            i-Butyl        CH.sub.2 CH.sub.3    18    Cbz            i-Butyl        CH(CH.sub.3).sub.2    19    Cbz            i-Butyl                                         ##STR281##    20    Q              i-Butyl                                         ##STR282##    21    Cbz                          ##STR283##    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2    22    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        CH(CH.sub.3).sub.2    23    Q              i-Butyl        CH(CH.sub.3).sub.2    24    Cbz            i-Butyl        C(CH.sub.3).sub.3    25    Q              i-Butyl        C(CH.sub.3).sub.3    26    Cbz                          ##STR284##    C(CH.sub.3).sub.3    27    Q                          ##STR285##    C(CH.sub.3).sub.3    28    Cbz            (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    29    Q              (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    30    Cbz            CH.sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    31    Q              CH.sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    32    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    33    Cbz            (CH.sub.2).sub.2 C.sub.6 H.sub.5                                        C(CH.sub.3).sub.3    34    Cbz            n-Butyl        C(CH.sub.3).sub.3    35    Cbz            n-Pentyl       C(CH.sub.3).sub.3    36    Cbz            n-Hexyl        C(CH.sub.3).sub.3    37    Cbz                          ##STR286##    C(CH.sub.3).sub.3    38    Cbz            CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    39    Q              CH.sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    40    Cbz                          ##STR287##    C(CH.sub.3).sub.3    41    Cbz            CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3                                        C(CH.sub.3).sub.3    42    Cbz                          ##STR288##    C(CH.sub.3).sub.3    43    Cbz                          ##STR289##    C(CH.sub.3).sub.3    44    Cbz            (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    45    Q              (CH.sub.2).sub.2 C(CH.sub.3).sub.3                                        C(CH.sub.3).sub.3    46    Cbz            (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    47    Q              (CH.sub.2).sub.4 OH                                        C(CH.sub.3).sub.3    48    Q                          ##STR290##    C(CH.sub.3).sub.3    49    Q                          ##STR291##    C(CH.sub.3).sub.3    50           ##STR292##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    51           ##STR293##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    52           ##STR294##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    53           ##STR295##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    54           ##STR296##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    55           ##STR297##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    56           ##STR298##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    57           ##STR299##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    58           ##STR300##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    59           ##STR301##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    60           ##STR302##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    61           ##STR303##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    62           ##STR304##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    63           ##STR305##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    64           ##STR306##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    65           ##STR307##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    66           ##STR308##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    67           ##STR309##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    68           ##STR310##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    69           ##STR311##    CH.sub.2 CH(CH.sub.3).sub.2                                        C(CH.sub.3).sub.3    __________________________________________________________________________     .sup.a benzyloxycarbonyl     .sup.b 2quinolinylcarbonyl

                                      TABLE 35    __________________________________________________________________________     ##STR312##    Entry         A                   R.sup.3    R.sup.4    __________________________________________________________________________     1   CbzVal              i-amyl     tBu     2   CbzLeu              i-amyl     t-Bu     3   CbzIle              i-amyl     t-Bu     4   AcD-homo-Phe        i-Bu       n-Bu     5   QuiOrn (γ-Cbz)                              ##STR313##                                        t-Bu     6   CbzAsn              CH.sub.2 CHCH.sub.2                                        t-Bu     7   Acetyl-t-BuGly      i-amyl     t-Bu     8   AcetylPhe           i-amyl     t-Bu     9   AcetylIle           i-amyl     t-Bu    10   AcetylLeu           i-amyl     t-Bu    11   AcetylHis           i-amyl     t-Bu    12   AcetylThr           i-amyl     t-Bu    13   AcetylNHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    14   CbzAsn              i-amyl     t-Bu    15   CbzAla              i-amyl     t-Bu    16   CbzAla              i-amyl     t-Bu    17   Cbz-beta-cyanoAla   i-amyl     t-Bu    18   Cbz-t-BuGly         i-amyl     t-Bu    19   Q-t-BuGly           i-amyl     t-Bu    20   QSCH.sub.3 CYS      i-amyl     t-Bu    21   CbzSCH.sub.3 Cys    i-amyl     t-Bu    22   QAsp                i-amyl     t-Bu    23   Cbz(NHCH(C(CH.sub.3).sub.2 (SCH.sub.3))C(O)                             i-amyl     t-Bu    24   CbzEtGly            i-amyl     t-Bu    25   CbzPrGly            i-amyl     t-Bu    26   CbzThr              i-amyl     t-Bu    27   QPhe                i-amyl     t-Bu    28   CbzPhe              i-amyl     t-Bu    29   Cbz NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    30   Q NHCH(CH.sub.2 C(O)NHCH.sub.3 !C(O)                             i-amyl     t-Bu    __________________________________________________________________________

                  TABLE 36    ______________________________________     ##STR314##    Entry       R.sup.1    ______________________________________    1           CH.sub.2 SO.sub.2 CH.sub.3    2           (R)CH(OH)CH.sub.3    3           CH(CH.sub.3).sub.2    4           (R, S)CH.sub.2 SOCH.sub.3    5           CH.sub.2 SO.sub.2 NH.sub.2    6           CH.sub.2 SCH.sub.3    7           CH.sub.2 CH(CH.sub.3).sub.2    8           CH.sub.2 CH.sub.2 C(O)NH.sub.2    9           (S)CH(OH)CH.sub.3    10          CH.sub.2 C CH    11          CH.sub.2 CCH.sub.2    ______________________________________

                  TABLE 37    ______________________________________     ##STR315##    Entry    R.sup.2       A    ______________________________________     1       n-Bu          CbzAsn     2       cyclohexylmethyl                           CbzAsn     3       n-Bu          Boc     4       n-Bu          Cbz     5       C.sub.6 H.sub.5 CH.sub.2                           Boc     6       C.sub.6 H.sub.5 CH.sub.2                           Cbz     7       C.sub.6 H.sub.5 CH.sub.2                           benzoyl     8       cyclohexylmethyl                           Cbz     9       n-Bu          QAsn    10       cyclohexylmethyl                           QAsn    11       C.sub.6 H.sub.5 CH.sub.2                           CbzIle    12       C.sub.6 H.sub.5 CH.sub.2                           QIle    13       C.sub.6 H.sub.5 CH.sub.2                           Cbz-t-BuGly    14       C.sub.6 H.sub.5 CH.sub.2                           Q-t-BuGly    15       C.sub.6 H.sub.5 CH.sub.2                           CbzVal    16       C.sub.6 H.sub.5 CH.sub.2                           QVal    17       2-naphthylmethyl                           CbzAsn    18       2-naphthylmethyl                           QAsn    19       2-naphthylmethyl                           Cbz    20       n-Bu          CbzVal    21       n-Bu          QVal    22       n-Bu          QIle    23       n-Bu          Cbz-t-BuGly    24       n-Bu          Q-t-BuGly    25       p-F(C.sub.6 H.sub.4)CH.sub.2                           QAsn    26       p-F(C.sub.6 H.sub.4)CH.sub.2                           Cbz    27       p-F(C.sub.6 H.sub.4)CH.sub.2                           CbzAsn    28       C.sub.6 H.sub.5 CH.sub.2                           Cbz-propargylglycine    29       C.sub.6 H.sub.5 CH.sub.2                           Q-propargylglycine    30       C.sub.6 H.sub.5 CH.sub.2                           acetyl-proparglyglycine    31       i-Bu          CbzAsn    ______________________________________

                                      TABLE 38    __________________________________________________________________________     ##STR316##    R.sup.3               R.sup.4    __________________________________________________________________________    CH.sub.2 CH(CH.sub.3).sub.2                          C(CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                           ##STR317##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                           ##STR318##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                           ##STR319##    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                           ##STR320##    __________________________________________________________________________

                                      TABLE 39    __________________________________________________________________________     ##STR321##    Entry        R                                     R.sub.1    __________________________________________________________________________     1         ##STR322##                           CH.sub.3     2         ##STR323##                           CH.sub.3     3         ##STR324##                           CH(CH.sub.3).sub.2     4         ##STR325##                           CH(CH.sub.3).sub.2     5         ##STR326##                           C(CH.sub.3).sub.3     6         ##STR327##                           CH.sub.3     7         ##STR328##                           CH.sub.3     8         ##STR329##                           CH.sub.3     9         ##STR330##                           CH.sub.3    10         ##STR331##                           CH.sub.3    11         ##STR332##                           CH.sub.3    12         ##STR333##                           CH.sub.3    13         ##STR334##                           CH.sub.3    14         ##STR335##                           CH.sub.3    15         ##STR336##    16         ##STR337##    __________________________________________________________________________

                  TABLE 40    ______________________________________     ##STR338##    R.sup.1         R.sup.1'                 R.sup.1"  R    ______________________________________    H    H       H                            ##STR339##    H    H       H                            ##STR340##    H    CH.sub.3                 H                            ##STR341##    H    CH.sub.3                 CH.sub.3                            ##STR342##    H    H       CO.sub.2 CH.sub.3                            ##STR343##    H    H       H                            ##STR344##    H    H       H                            ##STR345##    H    H       CONH.sub.2                           Cbz    H    H       CONH.sub.2                           2-quinolinylcarbonyl    ______________________________________

                  TABLE 41    ______________________________________     ##STR346##    R                 R'          X    ______________________________________    R = H             R' = H      X = H    R = Me            R' = Me     X = H    R = H             R' = Me     X = H    R = Me            R' = Me     X = F    R = H             R' = Me     X = F    R = Cbz           R' = Me     X = H    R = H             R' = Bz     X = H    R + R' = pyrrole*             X = H    ______________________________________     *lle in place of tbutylglycine

                  TABLE 42    ______________________________________     ##STR347##     ##STR348##     ##STR349##    ______________________________________

                  TABLE 43    ______________________________________     ##STR350##     ##STR351##                      ##STR352##    ______________________________________    CH.sub.2 CH(CH.sub.3).sub.2                     CH(CH.sub.3).sub.2    CH.sub.2 CH(CH.sub.3).sub.2                     CH(CH.sub.2 CH.sub.3).sub.2    CH.sub.2 CH(CH.sub.3).sub.2                     CH(CH(CH.sub.3).sub.2).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                     CH(CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                     CH(CH.sub.2 CH.sub.3).sub.2    CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                      ##STR353##     ##STR354##      CH(CH.sub.3).sub.2     ##STR355##      CH (CH.sub.2 CH.sub.3).sub.2     ##STR356##                      ##STR357##     ##STR358##                      ##STR359##     ##STR360##      CH(CH.sub.3) (t-Bu)     ##STR361##                      ##STR362##     ##STR363##                      ##STR364##     ##STR365##                      ##STR366##     ##STR367##                      ##STR368##     ##STR369##                      ##STR370##     ##STR371##                      ##STR372##     ##STR373##                      ##STR374##    ______________________________________

                  TABLE 44    ______________________________________     ##STR375##    Acyl Group (R)    ______________________________________    benzyloxycarbonyl    tert-butoxycarbonyl    acetyl    2-quinoylcarbonyl    phenoxyacetyl    benzoyl    methyloxaloyl    pivaloyl    trifluoracetyl    bromoacetyl    hydroxyacetyl    morpholinylacetyl    N,N-dimethylaminoacetyl    N-benzylaminoacetyl    N-phenylaminoacetyl    N-benzyl-N-methylaminoacetyl    N-methyl-N-(2-hydroxyethyl)aminoacetyl    N-methylcarbamoyl    3-methylbutyryl    N-isobutylcarbamoyl    succinoyl (3-carboxypropionyl)    carbamoyl    N-isobutylamino acetyl    N,N-diethylamino acetyl    N-(2-methoxyethyl)aminoacetyl    N-(S-α-methylbenzyl)aminoacetyl    N-(R-α-methylbenzyl)amino acetyl    N-(S-2-tetralin)amino acetyl    N-(R-2-teralin)amino acetyl    N-pyrrolidinylacetyl    N-methyl-N-(2-pyridylethyl)amino acetyl    N-tetrahydroisoquinolylaminoacetyl    N-p-methoxybenzylamino acetyl    ______________________________________

                  TABLE 45    ______________________________________     ##STR376##    R'    ______________________________________    CH.sub.3    CH.sub.3 CH.sub.2    CH.sub.3 CH.sub.2 CH.sub.2    PhCH.sub.2 CH.sub.2    PhCH.sub.2    Ph    (CH.sub.3).sub.2 CH    HOCH.sub.2 CH.sub.2     ##STR377##     ##STR378##     ##STR379##    CH.sub.2CHCH.sub.2    ______________________________________

                  TABLE 46    ______________________________________     ##STR380##           R'   R.sub.1    ______________________________________           CH.sub.3                CH(CH.sub.3).sub.2           CH.sub.3                C(CH.sub.3).sub.3    ______________________________________

                                      TABLE 47    __________________________________________________________________________     ##STR381##    R.sup.1  R.sup.30                R.sup.31                    R.sup.32                       X' R.sup.33                                  R.sup.34    __________________________________________________________________________    H        H  H   H  N  H       H    H        H  H   H  O  H       --    H        H  H   H  O  CH.sub.3                                  --    CH.sub.3 H  H   H  N  H       H    CH.sub.3 H  H   H  O  H       --    H        H  CH.sub.3                    H  N  H       H    H        H  CH.sub.3                    H  O  H       --    CH.sub.3 CH.sub.3                H   H  N  H       H    CH.sub.3 CH.sub.3                H   H  O  H       --    CH.sub.3 CH.sub.3                H   H  O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    H        H  CH.sub.3                    CH.sub.3                       N  H       H    H        H  CH.sub.3                    CH.sub.3                       O  H       --    H        H  CH.sub.3                    CH.sub.3                       O  CH.sub.2 C.sub.6 H.sub.4 OCH.sub.3                                  --    CH.sub.3 H  CH.sub.3                    H  N  H       H    CH.sub.3 H  CH.sub.3                    H  N  H       CH.sub.3    CH.sub.3 H  CH.sub.3                    H  N  CH.sub.3                                  CH.sub.3    CH.sub.3 H  CH.sub.3                    H  O  H       --    CH.sub.3 H  CH.sub.3                    H  N  H       CH.sub.2 C.sub.6 H.sub.5 OCH.sub.3    OH       H  H   H  N  H       H    OH       H  H   H  O  H       --    H        H  OH  H  N  H       H    H        H  OH  H  O  H       --    CH.sub.2 H  H   H  N  H       H    CH.sub.2 C(O)NH.sub.2             H  H   H  N  H       H    CH.sub.2 C(O)NH.sub.2             H  H   H  O  H       --    CH.sub.2 C(O)NH.sub.2             H  H   H  O  CH.sub.3                                  --    CH.sub.2 Ph             H  H   H  N  H       H    CH.sub.3 H  CH.sub.3                    CH.sub.3                       N  H       H    CH.sub.3 H  CH.sub.3                    CH.sub.3                       N  H       --    CH.sub.3 H  CH.sub.3                    CH.sub.3                       O  H       CH.sub.3    CH.sub.3 H  CH.sub.3                    CH.sub.3                       N  CH.sub.3                                  CH.sub.3    __________________________________________________________________________

                  TABLE 48    ______________________________________     ##STR382##     ##STR383##     ##STR384##     ##STR385##    ______________________________________

The compounds of the present invention areeffective antiviral compoundsand, in particular, areeffective inhibitors of retroviruses,particularly,lentroviruses as shown above. Thus, the subjectcompoundsare effective inhibitors of HIV. It is contemplated thatthesubject compounds will also inhibit other strains ofHIV, such as HIV-2and other viruses such as, for example,human T-cell leukemia virus,feline leukemia virus, simiamimmunodeficiency virus, respiratorysyncitial virus,hepadnavirus, cytomegalovirus and picornavirus. Thus,thesubject compounds are effective in the treatment and/orproplylaxis ofretroviral infections.

Compounds of the present can possess one or moreasymmetric carbon atomsand are thus capable of existing inthe form, of optical isomers as wellas in the form ofracemic or nonracemic mixtures thereof. Theopticalisomers can be obtained by resolution of the racemicmixturesaccording to conventional processes, for exampleby formation ofdiastereoisomeric salts by treatment withan optically active acid orbase. Examples of appropriateacids are tartaric, diacetyltartaric,dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid andthenseparation of the mixture of diastereoisomers bycrystallizationfollowed by liberation of the opticallyactive bases from these salts. Adifferent process forseparation of optical isomers involves the use of achiralchromatography column optfinally chosen to maximize theseparationof the enantiomers. Still another availablemethod involves synthesis ofcovalent diastereoisomericmolecules by reacting compounds of Formula Iwith anoptically pure acid in an activated form or an opticallypureisocyanate. The synthesized diastereoisomers can beseparated byconventional means such as chromatography,distillation, crystallizationor sublimation, and thenhydrolyzed to deliver the enantiomericaly purecompound.The optically active compounds of Formula I can likewisebeobtained by utilizing optically active starting materials.Theseisomers may be in the form of a free acid, a freebase, an ester or asalt.

The compounds of the present invention can beused in the form of saltsderived from inorganic or organicacids. These salts include but are notlimited to thefollowing: acetate, adipate, alginate, citrate,aspartate,benzoate, benzenesulfonate, bisulfate, butyrate,camphorate,camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate,ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate,heptanoate,hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate,nicotinate, 2-naphthalenesulfonate,oxalate, palmoate, pectinate,persulfate,3-phenylpropionate, picrate, pivalate, propionate,succinate,tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, thebasic nitrogen-containing groupscan be quaternized with such agents aslower alkyl halides,such as methyl, ethyl, propyl, and butylchloride,bromides, and iodides; dialkyl sulfates like dimethyl,diethyl,dibutyl, and diamyl sulfates, long chain halidessuch as decyl, lauryl,myristyl and stearyl chlorides,bromides and iodides, aralkyl halideslike benzyl andphenethyl bromides, and others. Water or oil-solubleordispersible products are thereby obtained.

Examples of acids which may be employed to formpharmaceuticallyacceptable acid addition salts includesuch inorganic acids ashydrochloric acid, sulphuric acidand phosphoric acid and such organicacids as oxalic acid,maleic acid, succinic acid and citric acid. Otherexamplesinclude salts with alkali metals or alkaline earth metals,suchas sodium, potassium, calcium or magnesium or withorganic bases.

Total daily dose administered to a host insingle or divided doses my bein amounts, for example,from 0.001 to 10 mg/kg body weight daily andmore usually0.01 to 1 mg. Dosage unit compositions my containsuchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may becombined with the carriermaterials to produce a singledosage form will vary depending upon thehost treated andthe particular mode of administration.

The dosage regimen for treating a diseasecondition with the compoundsand/or compositions of thisinvention is selected in accordance with avariety offactors, including the type, age, weight, sex, diet andmedicalcondition of the patient, the severity of thedisease, the route ofadministration, pharmacologicalconsiderations such as the activity,efficacy,pharmacokinetic and toxicology profiles of theparticularcompound employed, whether a drug delivery system isutilizedand whether the compound is administered as partof a drug combination.Thus, the dosage regimen actuallyemployed may vary widely and thereforemy deviate from thepreferred dosage regimen set forth above.

The compounds of the present invention may beadministered orally,parenterally, by inhalation spray,rectally, or topically in dosage unitformulationscontaining conventional nontoxic pharmaceuticallyacceptablecarriers, adjuvants, and vehicles as desired.Topical administration mayalso involve the use oftransdermal administration such as transdermalpatches oriontophoresis devices. The term parenteral as usedhereinincludes subcutaneous injections, intravenous,intramuscular,intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterileinjectable aqueous oroleaginous suspensions my beformulated according to the known art usingsuitabledispersing or wetting agents and suspending agents. Thesterileinjectable preparation may also be a sterileinjectable solution orsuspension in a nontoxicparenterally acceptable diluent or solvent, forexample, asa solution in 1,3-butanediol. Among the acceptablevehiclesand solvents that may be employed are water,Ringer's solution, andisotonic sodium chloride solution.In addition, sterile, fixed oils areconventionallyemployed as a solvent or suspending medium. Forthispurpose any bland fixed oil may be employed includingsynthetic mono-or diglycerides. In addition, fatty acidssuch as oleic acid find use inthe preparation ofinjectables.

Suppositories for rectal administration of thedrug can be prepared bymixing the drug with a suitablenonirritating excipient such as cocoabutter andpolyethylene glycols which are solid at ordinarytemperaturesbut liquid at the rectal temperature and willtherefore melt in therectum and release the drug.

Solid dosage forms for oral administration mayinclude capsules, tablets,pills, powders, and granules.In such solid dosage forms, the activecompound may beadmixed with at least one inert diluent such assucroselactose or starch. Such dosage forms may also comprise, asinnormal practice, additional substances other than inertdiluents, e.g.,lubricating agents such as magnesiumstearate. In the case of capsules,tablets, and pills, thedosage forms may also comprise buffering agents.Tabletsand pills can additionally be prepared with entericcoatings.

Liquid dosage forms for oral administration mayinclude pharmaceuticallyacceptable emulsions, solutions,suspensions, syrups, and elixirscontaining inert diluentscommonly used in the art, such as water. Suchcompositionsmay also comprise adjuvants, such as wettingagents,emulsifying and suspending agents, and sweetening,flavoring, andperfuming agents.

While the compounds of the invention can beadministered as the soleactive pharmaceutical agent, theycan also be used in combination withone or moreimmunomodulators, antiviral agents or otherantiinfectiveagents. When administered as a combination, thetherapeuticagents can be formulated as separatecompositions which are given at thesame time or differenttimes, or the therapeutic agents can be given as asinglecomposition.

The foregoing is merely illustrative of theinvention and is not intendedto limit the invention to thedisclosed compounds. Variations and changeswhich areobvious to one skilled in the art are intended to be withinthescope and nature of the invention which are defined inthe appendedclaims.

The preceding examples can be repeated withsimilar success bysubstituting the generically orspecifically described reactants and/oroperatingconditions of this invention for those used in theprecedingexamples.

From the foregoing description, one skilled inthe art can easilyascertain the essential characteristicsof this invention, and withoutdeparting from the spiritand scope thereof, can make various changesandmodifications of the invention to adapt it to varioususages andconditions.

What is claimed is:
 1. Compound represented by the formula: ##STR386##wherein R' represents hydrogen and radicals as defined for R³, andaralkoxycarbonylalkyl and aminocarbonylalkyl or aminoalkyl radicals,wherein said amino group may be mono- or disubstituted withsubstitutents selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, hetercycloalkyl andheterocycloalkylalkyl radicals;R¹ represents hydrogen, --CH₂ SO₂ NH₂,--CO₂ CH₃, --CH₂ CO₂ CH₃, --CONH₂, --CONHCH₃, CON(CH₃)₂, --CH₂ CONHCH₃,--CH₂ CON(CH₃)₂, alkyl, alkenyl, alkynyl and cycloalkyl radicals andamino acid side chains selected from asparagine, S-methyl cysteine andthe corresponding sulfoxide and sulfone derivatives thereof, glycine,leucine, isoleucine, allo-isoleucine, tert-leucine, phenylalanine,ornithine, alanine, histidine, norleucine, glutamine, valine, threonine,serine, aspartic acid, beta-cyano, alanine and allo-threonine sidechains; R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl radicals, --NO₂, OR⁹ and SR⁹ wherein R⁹ representshydrogen and alkyl radicals, and halogen radicals; R³ represents alkyl,alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstitutedaminoalkyl radicals where said substitutents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroalkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals; R⁴ and R⁵,independently represent hydrogen and radicals as defined by R³, or R⁴and R⁵ together with the carbon atom to which they are bonded representcycloalkyl heterocycloalkyl, heteroaryl and aryl radicals; R²⁰ and R²¹represent radicals as defined for R¹ ; and X represents O and C(R¹⁷)wherein R¹⁷ represents hydrogen and alkyl radicals, provided that when Xis O, R⁵ is absent; and Y and Y' independently represent O and S. 2.Compound of claim 1 wherein t is O.
 3. Compound of claim 1 wherein R¹represents hydrogen and alkyl radicals.
 4. Compound of claim 1 whereinR¹ represents alkyl radicals having from 1 to about 4 carbon atoms. 5.Compound of claim 1 herein R¹ represents methyl, ethyl, isopropyl andt-butyl radicals.
 6. Compound of claim 1 wherein R²⁰ and R²¹independently represent hydrogen and alkyl radials.
 7. Compound of claim1 wherein R²⁰ and R²¹ independently represent hydrogen and methylradicals.
 8. Compound of claim 1 wherein R²⁰ is hydrogen and R²¹ is analkyl radical.
 9. Compound of claim 1 wherein R' represents alkyl, aryland aralkyl radicals.
 10. Compound of claim 1 wherein R' is selectedfrom methyl and phenethyl radicals.
 11. Compound of claim 1 wherein R²represents alkyl, cycloalkylalkyl and aralkyl radicals, which radicalsare optionally substituted with halogen radicals and radicalsrepresented by the formula --OR⁹ and --SR⁹ wherein R⁹ representshydrogen and alkyl radicals.
 12. Compound of claim 1 wherein R²represents alkyl, cycloalkylalkyl and aralkyl radicals.
 13. Compound ofclaim 1 wherein R² represents aralkyl radicals.
 14. Compound of claim 1wherein R² represents CH₃ SCH₂ CH₂ -, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals. 15.Compound of claim 1 wherein R² represents an n-butyl and iso-butylradicals.
 16. Compound of claim 1 wherein R² represents benzyl,4-fluorobenzyl, and 2-naphthylmethyl radicals.
 17. Compound of claim 1wherein R² represents a cyclohexylmethyl radical.
 18. Compound of claim1 wherein X is carbon and R³, R⁴ and R⁵ independently represent alkyl,alkenyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, aralkyl and heteroaralkyl radicals. 19.Compound of claim 18 wherein R⁵ represents hydrogen when X is C and R⁵is absent when X is O.
 20. Compound of claim 18 wherein R³ and R⁴independently represent alkyl and alkenyl radicals.
 21. Compound ofclaim 19 wherein R³ and R⁴ independently represent alkyl andhydroxyalkyl radicals.
 22. Compound of claim 19 wherein R³ and R⁴independently represent alkyl, cycloalkyl and cycloalkylalkyl radicals.23. Compound of claim 19 wherein R³ and R⁴ independently representalkyl, heterocycloalkyl and heterocycloalkylalkyl radicals.
 24. Compoundof claim 19 wherein R³ and R⁴ independently represent alkyl, aryl andaralkyl radicals.
 25. Compound of claim 19 wherein R³ and R⁴independently represent alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, andheteroaralkyl radicals.
 26. Compound of claim 1 wherein R³ representsalkyl radicals having from about 2 to about 5 carbon atoms.
 27. Compoundof claim 1 wherein R³ and R⁴ independently represent i-propyl, i-butyl,neo-pentyl, i-amyl, t-butyl and n-butyl radicals.
 28. Compound of claim1 wherein X is carbon and R³, R⁴ and R⁵ independently represent alkylradicals having from about 2 to about 5 carbon atoms, cycloalkylalkylradicals, aralkyl radicals, heterocycloalkylalkyl radicals andheteroaralkyl radicals.
 29. Compound of claim 1 wherein R³ representsbenzyl, para-fluorobenzyl, para-methoxybenzyl, para-methylbenzyl, and2-naphthylmethyl radicals and R⁴ represents t-butyl.
 30. Compound ofclaim 1 wherein R³ is cyclohexyl methyl and R⁴ is t-butyl.
 31. Compoundof claim 1 wherein R³ is i-amyl and R⁴ is t-butyl.
 32. Compound of claim1 wherein R³ is i-butyl and R⁴ is t-butyl.
 33. Compound of claim 1wherein R³ is n-butyl and R⁴ is t-butyl.
 34. Compound of claim 1 whereinR³ is neo-pentyl and R⁴ is t-butyl.
 35. Compound of claim 1 wherein R⁴represents alkyl and cycloalkyl radicals.
 36. Compound of claim 1wherein X is carbon R⁵ represents hydrogen and alkyl and cycloalkylradicals.
 37. Compound of claim 1 wherein X is carbon and R⁴ and R⁵together with the carbon atom to which they are bonded representcycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals.
 38. Compoundof claim 1 wherein R³ represents heteroaralkyl radicals and R⁴ ist-butyl.
 39. Compound of claim 1 wherein R³ is a p-fluorobenzyl radicaland R⁴ is a t-butyl radical.
 40. A pharmaceutical composition comprisinga compound of claim 1 and a pharmaceutically acceptable carrier. 41.Method of inhibiting a retroviral protease comprising administering aprotease inhibiting amount of a composition of claim
 40. 42. Method ofclaim 41 wherein the retroviral protease is HIV protease.
 43. Method oftreating a retroviral infection comprising administering an effectiveamount of a composition of claim
 40. 44. Method of claim 43 wherein theretroviral infection is an HIV infection.
 45. Method for treating AIDScomprising administering an effective amount of a composition of claim40.